MONOGRAPH FOR UKPID MERCURY ST Kolev N Bates National Poisons Information Service (London Centre) Medical Toxicology Unit Guy's & St Thomas' Hospital Trust Avonley Road London SE14 5ER UK This monograph has been produced by staff of a National Poisons Information Service Centre in the United Kingdom. The work was commissioned and funded by the UK Departments of Health, and was designed as a source of detailed information for use by poisons information centres. Peer review group: Directors of the UK National Poisons Information Service. 1. SUBSTANCE/PRODUCT NAME 1.1 Origin of the substance Naturally occurring. Mercury occurs in the Earth's crust, mainly in the form of sulphides. The red sulphide, cinnabar, is the main component of the mercury ores. It may contain up to 70% mercury. Mercury is also released into the environment by human activities e.g. combustion of fossil fuels, waste disposal and industrial activities. Organic mercury compounds released into the environment are often broken down to elemental mercury or mercuric compounds (Berlin, 1986). 1.2 Name Elemental mercury. Inorganic mercury compounds. 1.2.1 Main brand names/main trade names 1.2.2 Generic name Mercury (Hg). Inorganic mercury compounds include: mercuric chloride (HgCl2), mercurous chloride (Hg2Cl2), mercuric iodide red (HgI2), mercuric oxide red, yellow (HgO), mercuric sulphide black, red (HgS), mercuric nitrate (Hg(NO3)2, mercuric cyanide (Hg(CN)2) 1.2.3 Synonyms Metallic mercury: hydrargyrum, hydrargyrum depuratum, mercure (French), mercurio (Spanish, Italian), quecksilber (German), quicksilver. Synonyms of some inorganic mercuric compounds are: Mercuric chloride (HgCl2): corrosive sublimate, mercury bichloride, quecksilber chlorid (German), Sublimat (Czech), mercuric bichloride, mercuric dichloride, mercury bichloride, mercury dichloride, mercury (II) chloride, bichlorure de mercure (French), bichloride of mercury, chloride rtutnaty (Czech), chlorure di mercurique (French), cloruro di mercurio (Italian), cloruro mercurio (Spanish), dichloromercury, mercury perchloride. Mercurous chloride (Hg2Cl2): calomel, calomelanos, mild mercurous chloride, mercury monochloride, mercury protochloride, mercury subchloride, white precipitate. Mercuric iodide, red: mercury biniodide. Mercuric oxide red, yellow (HgO): red precipitate, yellow precipitate. Mercuric sulphide black, red (HgS): chinese red, cinnabar, vermilion. 1.2.4 Common names/street names Quicksilver. 1.3 Chemical group/family Elemental mercury. Inorganic mercury compounds 1.4 Substance identifier and/or classification by use 1.5 Reference numbers Metallic mercury CAS 7439-97-6 RTECS OV 4550000 EINECS 2311067 NCI C60399 UN 2809 Mercuric chloride (HgCl2) CAS 7487-94-7 RTECS OV 9100000 UN 1624 EINECS 2312998 NCI C60173 Mercurous chloride (HgCl2) CAS 7546-30-7 RTECS OV 8750000 EINECS 2314309 Mercuric iodide red (HgI2) CAS 7774-29-0 RTECS OW 5250000 UN 1638 EINECS 2318738 Mercuric oxide yellow (HgO) CAS 21908-53-2 RTECS OW 875000 UN 1641 EINECS 2446547 Mercuric sulphide red (HgS) CAS 1344-48-5 RTECS EINECS 2156963 1.6 Supplier/importer/agent/ licence holder Mercury and mercury compounds importers as listed in the UK importers database (UKIM) are: Seasafe Marine Clothing Ltd. Tomita UK Ltd. Alarmexpress Ltd Philips Components Ltd Durham c/o Philips Impex Ltd Hughes Microelectronics Europe Ltd Sharp Manufacturing Company UK 1.7 Presentation Some mercuric compounds used in laboratories are listed. Mercuric iodide, red Form crystalline Mercurous mercury as Hg < 0.1%, Soluble mercury salts < 0.05 as Hg. Pack sizes available: 25, 100 and 500 g. Mercuric chloride Form crystalline Pack sizes available: 25, 100, 500 g and 1 kg. Mercuric nitrate Standardised solution 0.010 milliequivalents per ml Pack sizes available: 100 ml. 1.8 Physico-chemical properties Molecular weight Mercury Hg = 200.59 Mercuric chloride HgCl2 = 271.5 Mercurous chloride Hg2Cl2 = 236.0 Mercuric iodide red HgI2 = 454.4 Mercuric oxide red HgO = 216.6 Mercuric sulphide red HgS = 232.7 Physical state Metallic mercury: shiny, silvery white very mobile liquid, easily divisible into globules, which readily volatiles on heating. Mercuric chloride: crystals, powder of granules. Mercurous chloride: powder. Mercuric iodide, red: powder. Mercuric oxide, red: crystalline powder of scales. Mercuric oxide, yellow: powder. Mercuric sulphide, red: powder, lumps, hexagonal crystals. Colour Metallic mercury: shiny, silvery white very mobile liquid. Mercuric chloride: white. Mercurous chloride: white. Mercuric iodide, red: red. Mercuric oxide, red: bright red or orange red. Mercuric oxide, yellow: yellow or orange yellow. Mercuric sulphide, red: bright red. Odour Odourless. Solubility in water and organic solvents Solubility in lipids in the order of 5-50 mg/L. Solubility in water approximately 60 mg Hg/L at 24°C. Solubility of the inorganic mercury salts is influenced by valence state and anionic component (Goyer, 1980). Mercuric salts like halides, sulphates and nitrates are water soluble, sulphide and oxides are not (Berlin, 1986). Metallic mercury: 20-30g/L in water, soluble in nitric acid, insoluble in dilute hydrochloric acid, hydrogen bromide, hydrogen iodide and cold sulphuric acid. Mercuric chloride: 69g/L in water, 476g/L in boiling water, soluble in ethanol, benzene, ether, glycerol, acetic acid, methanol, acetone, ethyl acetate, slightly soluble in carbon disulphide and pyridine. Mercurous chloride: 2 x 10-3 g/L in water, insoluble in alcohol and ether. Mercuric iodide, red: 0.06g/L, soluble in alcohol, ether, acetone, ethyl acetate, carbon disulphide, alkali iodides and chloroform. Mercuric oxide, red yellow: practically insoluble in water, soluble in dilute hydrochloric acid and nitric acid, alkali cyanides or iodides, slowly in solutions of alkali bromides, insoluble in alcohol. Mercuric sulphide, red: practically insoluble in water. Autoignition temperature Not relevant. Boiling point Metallic mercury: 356.6°C Mercuric chloride: 302°C Mercurous chloride: NA Mercuric iodide, red: about 300°C, sublimes Mercuric oxide, red: NA Mercuric oxide, yellow: NA Mercuric sulphide, red: NA Density Metallic mercury: 13.59 g/cm2 Mercuric chloride: 5.4 g/cm2 Mercurous chloride: 7.15 g/cm2 Mercuric iodide, red: 6.28 g/cm2 Mercuric oxide, red: 11.14 g/cm2 Vapour pressure Metallic mercury 2 x 10-3 mm at 25°C. Relative vapour density Metallic mercury volatile. A saturated atmosphere of mercuric vapour contains approximately 18 mg Hg/m3 at 24°C. Reactivity Metallic mercury: reacts with ammonia, amines, acetylene and oxalic acids to form compounds that are sensitive to mechanical shock. Reacts with many metals except iron to form amalgams. Mercuric chloride: incompatible with formates, sulphites, hypophosphites, phosphates, sulphides, albumin, gelatin, alkalies, alkaloid salts, ammonia, antimony and arsenic, bromides, borax, carbonates, iron, copper, lead, silver salts. Mercurous chloride: incompatible with bromides, iodides, alkali chlorides, sulphates, sulphites, hydroxides, ammonia, cocaine, cyanides, copper salts, hydrogen peroxides, iodine, lead salts, silver salts and sulphides. Mercuric oxide, yellow: incompatible with reducing agents. Many mercury compounds decompose in light and should therefore be stored in the dark. 1.9 Hazard/risk classification 1.10 Uses Approximately 25% of the annual production of mercury is consumed by the chloralkali industry, 20% is used in electrical equipment, 15% in paints, 10% in measurement and control systems such as thermometers and sphygmomanometers, 5% in agriculture, 3% in dentistry (dental amalgam), and 2% in laboratories. The remaining 20% includes military uses such as detonators, mercury containing catalysts, preservatives in the paper-pulp industry, pharmaceuticals, in photography as an intensifying agent and others (Korringa and Hagel, 1974). Mercury was replaced as a preservative in emulsion paint in the UK by substances such as ammonia and subsequently organic based preservatives, over a period of years from the mid-fifties to the late seventies. Inorganic mercury compounds have been used in medicine for centuries, but their use has been greatly reduced because of their toxicity. Mercuric chloride was used as a laxative and applied topically as an antibacterial agent. It was also used in the treatment of syphilis before the advent of antibiotics. Mercury compounds have been used as an irrigation solutions in the management of carcinoma. Mercurials have also been used as spermicides. Mercurius solubilis (Merc. Sol.) a nitrated oxide of mercury is used in homoeopathic medicine. Mercury compounds (particularly mercuric iodide) have been used in skin lightening creams and soaps. Such products are banned but may be found in imported products or those intended for sale overseas. 1.11 Toxicokinetics 1.11.1 Absorption Oral: Metallic mercury is poorly absorbed after ingestion at a rate related to the vaporisation (0.01%) and it is generally thought to be of no toxicological consequence (Goyer, 1980), unless there is significant delay in passage through the gastrointestinal tract or the patient is exposed chronically. Inorganic soluble mercuric compound are readily absorbed into the circulation e.g. mercurous chloride (up to 10%) (WHO, 1991). A considerable proportion can remain fixed to the intestinal mucosa and intestinal contents. Insoluble compounds undergo oxidation to soluble absorbable compounds (Winship, 1985). Some compounds which are particularly insoluble are poorly absorbed e.g. cinnabar. However, chronic low dose exposure to these compounds may lead to mercury intoxication (Kang-Yum and Oransky, 1992). Inhalation: Mercury vapour is efficiently absorbed from the alveolar air (about 80%) (WHO, 1991) due to the rapid diffusion of the vapour through the alveolar membrane. Dermal: Elemental mercury may be readily absorbed if applied to the skin in suitable form. When applied as ointment, up to 31% of the amount applied was excreted (Oehme, 1972). In animal studies up to 8% of mercuric chloride applied to the skin was absorbed within 5 hours (Berlin, 1986). Vaginal: Mercury compounds presented in vaginal jellies are easily absorbed and retained in the body (Oehme, 1972). 1.11.2 Distribution Absorbed mercury passes into the circulation where about half of it is bound to albumin in the plasma (in combination with sulphydryl groups), the other half enters red blood cells. It is then rapidly distributed to the tissues and within a few hours the highest concentration is found in the kidneys. The liver, blood, spleen, respiratory mucosa, small and large intestine, skin, salivary glands, heart, skeletal muscle, brain and lungs contain decreasing amounts. Mercury is stored in the bone, bone marrow and liver for a short time. A special affinity for absorbed mercury in the frontal and basal cerebral regions of the brain has been noted. A week after exposure 85-95% of all mercury in the body is stored in the kidney. With continued absorption the concentration in the kidney increases. Further absorption results in higher levels in other organs without affecting renal levels (Winship, 1985). Since organic mercury is concentrated in the erythrocytes and inorganic is not, the ratio of the amount in the red blood cells and plasma will indicate whether the patient has been exposed to organic or inorganic mercury. Mercury vapour crosses cell membranes much more rapidly than divalent compounds, a significant amount of the vapour reaches the brain before it is oxidised. Exposure to mercury vapour results in concentrations in the brain which are 10 times higher than those following an equivalent dose of inorganic mercuric salts (Winship, 1985). The concentration of mercury in hair is about 300 times that in the blood, and the most recent growth of hair reflects past blood mercury levels. All forms of mercury cross the placenta to the foetus. Foetal uptake of elemental mercury in rats has been shown to be 10-40 times higher than uptake after exposure to inorganic compounds probably because of lipid solubility of mercury vapour (Goyer, 1980). 1.11.3 Biological half-life Biological half-life for inorganic mercury is about 40 days. For elemental mercury or mercury vapour the biological half-life is linear with a range of values from 35 to 90 days. The biological half-life is different for different organs. A fraction of the absorbed mercury will remain in the body for a longer time (e.g. years in the brain) (WHO, 1991). 1.11.4 Metabolism Metallic mercury is oxidised to divalent mercury after absorption to tissues and this is probably mediated by catalases. Inhaled mercury vapour absorbed into red blood cells is transformed to divalent mercury. However a proportion is also transformed as metallic mercury to more distal tissues, particularly to the brain where biotransformation may occur. 1.11.5 Elimination Mercury is excreted mainly in the urine but considerable amounts are also passed in the faeces through secretion by the gastrointestinal tract, particularly in the colon, bile and saliva, gastric and intestinal fluid. Mercuric mercury is also excreted by sweat, lachrimal and mammary glands (Berlin, 1986). Excretion begins soon after absorption and continues rapidly, with the tissue concentration falling at different rates. The best mathematical model seems to be a multicompartment model with at least two or more excretion rates and with one small compartment including the brain. Most of the mercury is excreted within a week but low levels may be found in the urine and faeces for months. Small amounts may be retained in the brain for a long period. Renal tissue tends to retain mercury, one week after exposure 60-70% of mercury is still present. 60-70% of the mercury is excreted as a sulphydryl mercury compound. The kinetics of clearance from the body have shown three distinct phases. In the first, 35% of the absorbed mercury with the half-time 3-4 days, accumulated in the liver and was excreted into the faeces and transported into the kidneys. In the second phase, 50% of the dose had a half-time of 30 days and was excreted in the urine following renal accumulation. The remaining 15%, with a half time of 100 days, was accounted for by renal excretion. 1.11.6 Special populations No data available. 2. SUMMARY 3. EPIDEMIOLOGY OF POISONING Occupational Human exposure to inorganic mercury is mainly occupational, most commonly associated with mercury vapour. It is often related to specific working conditions e.g. mining, spillage of mercury compounds on work clothes or in the working environment, handling of mercury salts in the chemical industry and laboratories (Berlin, 1986; Bluhm et al, 1992; Wide, 1986). Accidental Illicit gold extraction using mercury has also resulted in mercury poisoning in adults and children (Shamley and Sack, 1989; Moromisato et al, 1994). The mercury is mixed with quartz and gold, an amalgam is formed with the gold and this is then heated until the mercury evaporates off. Elevated levels of mercury were reported in 8 students following exposure to mercury vapour during an experiment. Fourteen others and the teacher had mercury levels below the normal concentration (Anon, 1988). There are several cases in the literature of mercury poisoning from spillage of metallic mercury in the home and inappropriate cleaning up of the chemical, particularly using a vacuum cleaner (Schwartz et al, 1992; McNeil et al, 1984; Muhlendahl, 1990; Bonhomme et al, 1996). Mercury poisoning has also occurred from ingestion of a button battery containing mercury (Mant et al, 1987). Toxicity has been reported following exposure to mercury vapour from a broken mercury expansion switch in a heating unit of an infant incubator (McLaughlin et al, 1980). Medicinal and cosmetic use Toxicity and deaths have occurred from the medicinal use of inorganic mercury compounds (Rajagopal and Hamilton,1984; Laundy et al, 1984). Poisoning has been reported following the use of mercury-containing skin lightening creams and soaps (Lauwerys et al, 1987; Dept of Pharmacology-Drug and Toxicology Information Service, 1990). Poisoning has also been reported following the use of traditional remedies (Kew et al, 1993; Perharic et al, 1994; Kang-Yum and Oransky, 1992). There are rare reports of mercury poisoning following aspiration of metallic mercury (Zimmerman, 1969). In some case only mild symptoms have developed (Wallach, 1972; Janus and Klein, 1982; Tsuji et al, 1970). Intentional Metallic and inorganic salts of mercury have also been used as a means of suicide (Winship, 1985), including deliberate intravenous, intra-arterial injection (Vale and Proudfoot, 1995) and subcutaneous injection (Hill, 1967). Dental amalgam Dental amalgam and the risk to human health has been the subject of several reviews (Goering et al, 1992; Fung and Molvar, 1992; Enwonwu, 1987; Mjor, 1994; Halbach, 1994; Aposhian et al, 1992). As well as mercury poisoning, dental amalgam has been claimed to cause multiple sclerosis, leukaemia, rheumatoid arthritis and numerous other disorders. Dental amalgam contains about 50% mercury with silver, copper, zinc and some other metals in small quantities. It has been used in dentistry for over 150 years. Amalgam is manufactured to be inert and biological inactive, but it is known that mercury vapour is given off with chewing and brushing of teeth. This vapour is then inhaled and swallowed. Uptake of mercury from dental amalgam has been demonstrated in sheep (Boyd et al, 1991) and monkeys (Hahn et al, 1990). In man postmortem studies have shown a higher concentration of mercury in the brain and kidney of subjects with amalgam fillings than in those without. One of the most important points raised by these reviews is that the effect of chronic low dose mercury exposure on man is not known. The currently available evidence suggests that when reasonable precautions are used dental amalgam is not a significant health hazard to dental workers or patients. There is however a need for more research. Table 1 gives the daily mercury retention in the general population (WHO, 1991). This includes organic mercury but it is clear that dental amalgam is the primary source of mercury in the general population. Table 1. Exposure source µg Hg/day absorbed Dental amalgam 3.0-17.0 Fish or seafood 2.34 Other food 0.25 Water 0.0035 Air 0.001 Daily mercury retention in the general population (WHO, 1991) 4. MECHANISM OF ACTION/TOXICITY 4.1 Mechanism Mercury compounds are highly potent but non-specific cellular poisons, that influence many vital processes involving proteins. Mercury ions are protein precipitants and as a result cause severe necrosis on direct contact with tissue. They have affinity for a number of cellular components essential for the function and survival of the cell such as enzymes, membrane proteins, nucleic acids and mitotic apparatus. Mercury interacts with sulphydryl groups and disulphide bonds of the membrane, as a result of which specific membrane transport is blocked and selective permeability of the membrane altered. Mercuric compounds are also immunotoxic and some have been shown to be strong sensitisers (Winship, 1985). Table 2 outlines the differential characteristics of inorganic and elemental exposure (from Young-Jin, 1994). Table 2 Elemental mercury Inorganic mercury Primary route of exposure Inhalation Oral, dermal Primary tissue distribution CNS, kidney Kidney Clearance Renal, GI Renal, GI Clinical effects CNS Tremor Tremor, erethism Pulmonary +++ - Gastrointestinal + +++ (corrosive) Renal + +++ Acrodynia + ++ Differential characteristics of inorganic and elemental mercury exposure (from Young-Jin, 1994) 4.2 Toxic dose Ingestion of 0.5 g mercuric chloride usually results in serious illness but rarely proves fatal. Doses of 1 g cause death in about 50% of cases and more than 1.5 g in nearly all cases. The prognosis has improved since the introduction of chelating agents (Bidstrup, 1964). Toxic effects are usually evident within 10-15 minutes of ingestion (Reynolds, 1983). Troen et al (1951) reported 18 cases of human poisoning after oral ingestion of a single dose of mercuric chloride, nine of which resulted in death. The lethal doses ranged from 29 mg/kg body weight to at least 50 mg/kg body weight. The most common autopsy findings in these cases were gastrointestinal lesions (ranging from mild gastritis to severe necrotic ulceration of the mucosa) and renal lesions that had resulted in renal failure. Clinical features of mercury poisoning did not occur following ingestion of 204g (15ml) of metallic mercury and all the mercury was passed in the faeces within 3 days (Wright et al, 1980). An adult who ingested about 3kg (220ml) of metallic mercury had elevated blood and urine levels of mercury but he developed only mild effects; six months later he returned with mild jaundice and impaired LFTs. In this case the mercury was cleared from the gut within 10 days (Lin and Lim, 1993). Acute mercury intoxication has been described after using 1/500 to 1/1000 solutions of mercuric chloride for peritoneal lavage (Laundy et al, 1984). A 17-year old woman developed acute mercury intoxication with renal failure after inserting 1 g mercuric chloride tablet into her vagina in order to induce abortion (Page et al, 1983). Micromercuralism has been reported after long term exposure to mercury concentration in the air of 0.05 mg/m3 (Berlin, 1986). 5. FEATURES OF POISONING 5.1 Acute poisoning 5.1.1 Ingestion Critical organs are the kidney and the intestinal tract. The corrosive effect of concentrated mercury salt solutions on the mucous membranes of the gastrointestinal tract causes extensive precipitation of proteins. Gastric pain and vomiting may ensue. As the compound passes to the lower regions of the gut, general abdominal pain and bloody diarrhoea with necrosis of the intestinal mucosae may occur. This may lead to circulatory collapse and death. If the patient survives the gastrointestinal tract damage renal failure due to necrosis of the proximal tubular epithelium occurs within 24 hours. Apart from the corrosive damage there may be also be local vasospasm due to activation of the angiotensin system (Berlin, 1986). 5.1.2 Inhalation Inhalation of mercury vapour is the most important route of uptake for elemental mercury. The lung is the critical organ upon accidental exposure to high concentrations of mercury vapour. Mercury vapour causes erosive bronchitis and bronchiolitis with interstitial pneumonitis. Victims usually develop respiratory insufficiency. These symptoms may be combined with signs caused by effects on the CNS, such as tremor or increased excitability. Workers acutely exposed (4-8 h) due to an accident exhibited chest pain, dyspnoea, cough, haemoptysis, and evidence of interstitial pneumonitis. The calculated elemental mercury concentration was 1.1 to 44 mg/m3 (WHO, 1991). 5.1.3 Skin exposure The soluble inorganic compounds of mercury are irritating to the skin and mucous membranes; this effect is particularly marked with mercuric chloride. Concentrations of 1-5% cause irritation, vesiculation and corrosion of the skin. Dilute solutions may produce irritation of sensitive skin. The water insoluble mercury compounds do not cause immediate skin reactions, but this may develop slowly as the compound is absorbed and the mercury ionised in the tissues. Mercurous salts are less corrosive than mercuric compounds. 5.1.4 Eye contact Mercurous and mercuric salts are corrosive to the eyes (Atterbury and Olson, 1990), the latter more so. 5.1.5 Parenteral exposure A 21 year old female injected metallic mercury subcutaneously into both thighs. Her blood concentration of mercury was elevated but she did not develop features of mercury poisoning (Hill, 1967). Acute mercury intoxication has been described after using 1/500 to 1/1000 solutions of mercuric chloride for peritoneal lavage (Laundy et al, 1984). 5.1.6 Other No data. 5.2 Chronic poisoning 5.2.1 Ingestion Cases of chronic poisoning with calomel (mercurous chloride) have been described. Signs and symptoms similar to those of poisoning with mixed exposure to mercury vapour and mercuric mercury were described. With chronic exposure to inorganic mercury the kidney is the critical organ. Symptoms such as increased salivation and inflammatory changes in the gums and black lines on the teeth, due to precipitation of mercuric sulphide can also appear. Two type of renal damage can occur: 1) a glomerular injury caused by the toxic effect of mercury on the cells of the basal membrane of the glomeruli. An autoimmune reaction is induced due to formation of antigen against the glomerular tissue, and a nephrotic syndrome develops with proteinuria and the classical signs of glomerulonephritis. 2) the other type of renal injury is tubular damage. Mercury accumulation causes necrosis and damage of the distal and middle portion of the proximal tubuli (Berlin, 1986). 5.2.2 Inhalation Chronic inhalation of mercury vapour the major effects are on the central nervous system. Early signs are not specific and have been termed asthenic-vegetative syndrome or micromercuralism, with symptoms such as weakness, fatigue, forgetfulness, anorexia, loss of weight, and disturbance of gastrointestinal tract function. At higher exposure levels, the characteristic mercurial tremor appears as a fine trembling of the muscles, interrupted by coarse shaking movements every few minutes. This begins peripherally in the fingers, eyelids, and lips and has the characteristics of intentional tremor. In progressive cases it may develop into generalised tremor involving the entire body, with intermittent violent chronic spasms of the extremities. This is often accompanied by changes in personality and behaviour, with loss of memory, increased excitability (erethism) severe depression, and even delirium and hallucinations. Another characteristic feature of mercury vapour intoxication is severe salivation and gingivitis (Goyer, 1980). Sporadic instances of proteinuria and even nephrotic syndrome may occur. EEG changes together with changes in visually evoke response in chronically exposed workers have been reported. ALA D hydratase activity in blood cells decreases and the cholinesterase activity in plasma markedly decreases with the increasing mercury excretion in urine. An increased frequency of aneuploidy in lymphocytes from workers exposed to mercury vapour has been described. Symptoms of poisoning may regress and disappear when exposure has ceased. However, in severe cases with long term exposure, persistent sequelae related to the nervous system are common. A long term exposure to mercury concentration in the air of 0.1 mg/m3 or higher, the probability of developing mercuralism increase. Exposure to metallic mercury may rarely produce sensitation, for example from amalgam teeth fillings. 5.2.3 Skin exposure Typical manifestations are erythema and contact dermatitis. Ammoniated mercury is a common cause. Mercury compounds give rise to a type IV cell-mediated delayed hypersensitivity reaction. There have been a few cases of allergic dermatitis among dental personnel (WHO, 1991). An idiosyncratic hypersensitivity reaction has been described, particularly in children. This syndrome called acrodynia or pink disease, is characterised by a generalised body rash. Other symptoms are: chills, swelling and irritation of the hands, feet, cheeks and nose, usually followed by desquamation, loss of hair and ulceration, hyperplasia and hyperkeratosis, irritability, sleeplessness, and profuse perspiration which may lead to dehydration. The perspiration is accompanied by dilated and enlarged sweat glands and desquamation of the sole and palms. Once mercury exposure ceases, the signs gradually disappear. Patients with acrodynia usually have increased levels of mercury in the urine (> 50 mg/L) (Berlin, 1986). In certain circumstances skin absorption may be responsible for the occurrence of systemic chronic toxicity. When applied as ointment, up to 31% of the amount applied was excreted (Oehme, 1972). In animal studies up to 8% of the mercuric chloride applied to the skin was absorbed within 5 hours (Berlin, 1986). 5.2.4 Eye contact Mercurialentis is the name given to an unusual appearance of the anterior surface of the lens seen in people exposed to mercury. The change in the lens consists of greyish or light-to-coffee brown granular discoloration, detected by slit-lamp examination. The change is bilateral and symmetrical, and the visual activity is unaffected. It has been seen in people who have had prolonged exposure. It was suggested that mercury is absorbed through the cornea circulates in the aqueous humour, and precipitates on the anterior surface of the lens. Mercurialentis is a manifestation of exposure but not necessary of toxic absorption (Winship, 1985). 5.2.5 Other Subcutaneous injection of metallic mercury resulted in the development of tender fluctuant abscess with surrounding erythema. Between 0.5 and 1 ml mercury was recovered in each side of injection. No symptoms or signs of mercury poisoning developed. However, the blood and urine mercury concentration were within the range encountered in chronic mercury poisoning (Hill, 1967). 5.3 Systematic description of clinical effects 5.3.1 Cardiovascular Acute: Tachycardia with dull heart sounds and a gallop rhythm have been reported secondary to severe pneumonitis after acute exposure to mercury vapour (Berlin, 1986). Chronic: EEG changes have been recorded in chronically exposed workers (Berlin, 1986). 5.3.2 Respiratory Acute: The lung is the critical organ in acute accidental exposure to high concentrations of mercury vapour. Mercury vapour causes erosive bronchitis and bronchiolitis with interstitial pneumonitis. Chest pain, dyspnoea, cough, haemoptysis, and evidence of interstitial pneumonitis have been reported (WHO, 1991), atelectasis, emphysema, haemorrhage and pneumothorax often follow (Winship, 1985). The cause of death is progressive respiratory failure. The mortality rate is higher in children than adults (Moutinho et al, 1981; Moromisato et al, 1994). Aspiration of metallic mercury may result in severe pulmonary toxicity or death (Zimmerman, 1969). In some case only mild symptoms have developed (Wallach, 1972; Janus and Klein, 1982; Tsuji et al, 1970). 5.3.3 Neurological Chronic: Most information focuses on effects on the CNS following occupational exposure. Characteristic signs are tremor, motor disturbances and mental deterioration. The most common psychiatric signs and symptoms are depression, irritability, and exaggerated response to stimulation, with excessive shyness, loss of confidence, vague fears, insomnia, emotional instability, forgetfulness and confusion. In advanced cases there may be loss of memory, hallucinations or intellectual deterioration, suicidal melancholia, or even manic-depressive psychoses. Tremors are common, a fine static tremor of the fingers, eyelids, lips and tongue develops and may progress to the arms and legs. The tremor may cause deterioration of the handwriting and the ability to perform other manipulative tasks. Intention tremor have also been reported. Slurred speech may developed. Four out of nine workers exposed to mercury vapour had clinical signs suggesting involvement of the peripheral nervous system in addition to the features of chronic poisoning. Electromyographic changes consistent with denervation were demonstrated in eight. Sensory effects are uncommon with poisoning by inorganic salts. However, constriction of visual fields, difficulties in counting objects at a low illumination and poor depth and colour perception have been reported in a patient with chronic mercury poisoning. 5.3.4 Gastrointestinal Acute: The gastrointestinal system is usually affected after acute exposure to inorganic mercury compounds (e.g. mercuric chloride). One of the earliest symptoms is metallic taste, followed by thirst, severe abdominal pain, vomiting and diarrhoea. The toxic effects are usually evident within 10-15 minutes of ingestion (Reynolds, 1983). Ashen discoloration of the mouth and pharynx are seen. Stomatitis develops in about 24 hours. Colitis with prolonged haemorrhagic diarrhoea may also occur. Chronic: Excessive salivation with loosening of the teeth is a sign of advanced poisoning, as is a blue line along the gum margin (Winship, 1985). 5.3.5 Hepatic Chronic: Disturbed liver function with raised serum alkaline phosphatase have been reported in 6 out of 70 patients following chronic use of ammoniated mercury ointment (Klaassen, 1980). 5.3.6.1 Renal Acute: Renal failure due to necrosis of the proximal tubular epithelium typically occurs within 24 hours after acute exposure to inorganic mercury compounds. Apart from the corrosive damage there may also be a local vasospasm due to activation of the angiotensin system (Berlin, 1986). Chronic: With chronic exposure to inorganic mercury the kidney is the critical organ. Symptoms such as increased salivation and inflammatory changes in the gums and black lines on the teeth, due to precipitation of mercuric sulphide can also appear. Two type of renal damage can occur: 1) a glomerular injury caused by the toxic effect of mercury on the cells of the basal membrane of the glomeruli. An autoimmune reaction is induced due to formation of antigen against the glomerular tissue, and a nephrotic syndrome develops with proteinuria and the classical signs of glomerulonephritis. 2) tubular damage may also occur. Mercury accumulation causes necrosis and damage of the distal and middle portion of the proximal tubuli (Berlin, 1986). WHO (1976) states that effects of elemental mercury on the kidney had been reported only at doses higher than those associated with the onset of the CNS toxicity sign and symptoms. Since then several new studies have been carried out, and kidney effects have been seen at lower exposure levels (WHO, 1991). 5.3.7 Endocrine and reproductive systems Enlargement of the thyroid gland has been reported but the incidence in relation to exposure to mercury is uncertain (Winship, 1985). 5.3.8 Dermatological The soluble inorganic compounds of mercury are irritating to the skin and mucous membranes; this effect is particularly marked with mercuric chloride. Concentrations of 1 to 5% cause irritation, vesication, and corrosion of the skin and mucous membranes, and much more diluted solutions may produce irritation to sensitive skin. Typical manifestations are erythema and contact dermatitis. Ammoniated mercury is commonly implicated (WHO, 1991). 5.3.9 Eye, nose, throat: local effects Acute: Mercurous and mercuric salts are corrosive to the eyes (Atterbury and Olson, 1990), the latter are more corrosive. Concentrations of 1 to 5% cause irritation, vesication, and corrosion of the skin and mucous membranes, and much more diluted solutions may produce irritation. Chronic: Mercurialentis is the name given to an unusual appearance of the anterior surface of the lens seen in people exposed to mercury. The change in the lens consists of greyish or light-to-coffee brown granular discoloration, detected by slit-lamp. The change is bilateral and symmetrical, and the visual activity is unaffected. It has been seen in people who have had prolonged exposure. It has been suggested that mercury is absorbed through the cornea circulates in the aqueous humor, and precipitates on the anterior surface of the lens. Mercurialentis is a manifestation of exposure but not necessary of toxic absorption (Winship, 1985). 5.3.10 Haematological Chronic: Anaemia may follow chronic exposure to inorganic and metallic mercury. Leucopenia, eosinophilia and thrombocytopenia have been reported rarely. Aplastic anaemia and death from bone marrow suppression have also been described (Winship, 1985). 5.3.11 Immunological Experimental studies on animals have shown that inorganic mercury may induce auto-immune glomerulonephritis in all species tested but not in all strains, indicating a genetic predisposition (WHO, 1991). 5.3.12 Metabolic Acute: Metabolic, acid base and fluid and electrolyte disturbances may developed secondary to severe vomiting and diarrhoea, or to acute renal failure after acute poisoning with inorganic mercury salts. 5.3.12.3 Others No data. 5.3.13 Allergic reactions Erythema and contact dermatitis may occur. Ammoniated mercury is commonly implicated. Mercury compounds give rise to a type IV cell-mediated delayed hypersensitivity reaction. There have been a few cases of allergic dermatitis among dental personnel (WHO, 1991). Allergic reactions have been reported with dental amalgam. Symptoms may occur within hours to several days after placement of amalgam restorations. Symptoms may be limited to areas of contact or be generalised, including eczema, urticaria and wheals on the face. Other symptoms reported include dryness and soreness of the throat and mouth, fever, hives, swelling of lips, tongue and mucosa. Most effects are self-limiting and resolve within 2 weeks (Fung and Molvar, 1992). 5.13.14 Other An idiosyncratic hypersensitivity reaction has been described, particularly in children. This syndrome called acrodynia or pinks disease, is characterised by generalised erythematous body rash. Other symptoms are chills, swelling and irritation of the hands, feet, cheeks and nose, usually followed by desquamation, loss of hair and ulceration, hyperplasia and hyperkeratosis, irritability, sleeplessness and profuse perspiration which may lead to dehydration. The perspiration is accompanied by dilated and enlarged sweat glands and desquamation of the sole and palms. Once mercury exposure ceases, the signs gradually disappear. Patients with acrodynia usually have increased levels of mercury in the urine (> 50 mg/L) (Berlin, 1986). 5.4 At risk groups 5.4.1 Elderly No special risk as human exposures are mainly occupational. 5.4.2 Pregnancy Sikorski et al (1987) reports a high frequency of foetal malformations among the children of dental staff. Of 117 pregnancies in the mercury exposed group, 28 pregnancies in 19 women led to spontaneous abortion (19 cases) and stillbirth (3 cases) and congenital malformations (5 cases of spina bifida and one case of intra-atrial defect). In non exposed controls, there were 7 cases of adverse pregnancy outcome in five women out of a total 63 pregnancies (30 women). Another study investigated the Swedish National registers for birth records. There was no tendency towards an elevated rate of malformations, abortions or stillbirth among dentists dental nurses and dental technicians. On balance it would seem likely that there is risk of teratogenicity or foetal toxicity following maternal exposure to mercury vapour or inorganic salts. 5.4.3 Children Acute mercury vapour inhalation is reported to have a higher mortality rate in children than in adults (Moutinho et al, 1981; Moromisato et al, 1994). In addition to the features of acute and chronic poisoning recorded in adults, an idiosyncratic reaction has been described in children. This syndrome called acrodynia or pink disease, is characterised by general body rash. Other symptoms are chills, swelling and irritation of the hands, feet, cheeks and nose, usually followed by desquamation, loss of hair and ulceration, hyperplasia and hyperkeratosis, irritability, sleeplessness, and perfuse perspiration which may lead to dehydration. The perspiration is accompanied by dilated and enlarged sweat glands and desquamation of the sole and palms. Once mercury exposure ceases, the signs gradually disappear. Patients with acrodynia usually have increased levels of mercury in the urine (> 50 mg/L) (Berlin, 1986). Renal tubular acidosis has been described in children. This disorder was caused by exposure to mercuric salts from application of an ointment containing ammoniated mercury. (Berlin, 1986). 5.4.4 Enzyme deficiencies No data available. 5.4.5 Enzyme induced No data available. 5.4.6 Occupations Exposure to mercury vapour occurs in a variety of industries: in mercury mining, levels as high as 5mg/m3 have been reported (Berlin, 1986), chloralkali factories range 10-50mg/m3, (WHO, 1991) instrument manufacturing, physics and medical laboratories, some exposure may also occur in dental surgeries. Common operations in which exposure to inorganic mercury may occur are as follows: 1) During use as a liquid cathode in electrolytic production of chlorine and caustic soda from brine. 2) During manufacture of inorganic and organic compounds for use as pesticides, antiseptics, germicides. Also miscellaneous applications as chemical intermediate. 3) Preparation of amalgams in dentistry, in chemistry processing and jewellery manufacture. 4) Manufacturing of mildew-proof paints and marine anti-fouling agents. 5) Manufacturing of batteries, lamps (fluorescent and mercury), power tubes, tungsten-molybdenum wire and rods. 6) Manufacturing of inorganic salts for use as catalysts in the production of urethanes, vinyl chloride monomers and other chemicals. 7) Manufacturing of instruments (e.g. thermometers, barometers with mercury as a working fluid). 8) Manufacturing of explosives and fireworks. 9) During use as a conductor during construction and maintenance of military and nuclear power systems, in mercury-stem boilers, and in air rectifiers. 10) During use and manufacturing of compounds for the pulp and paper industry as a control for biological growths. 11) During roasting and smelting operations, extraction of silver and gold, mining and subsequent refining of ore containing cinnabar (Aronow, 1990). 5.4.7 Others No data available. 6 MANAGEMENT 6.1 Decontamination Inhalation Immediately remove victim from exposure and give oxygen if available. After spill of metallic mercury, carefully clean up all liquid and discard contaminated carpeting or porous tile, or arrange for professional toxic cleanup with self contained vacuum system. Do not vacuum with home vacuum cleaner; this may disperse liquid mercury, increasing its airborne concentration. Ingestion of liquid mercury Because liquid mercury usually passes through the gastrointestinal tract system without being absorbed gut decontamination is not required. Following a very large intentional ingestion, particularly in a patient with multiple blind loops of bowel or intestinal perforation, there is a risk of chronic intoxication. Whole gut lavage, or even surgical removal may be necessary depending on X-ray evidence of large pockets of mercury. Ingestion of inorganic mercuric salts Perform gastric lavage. Do not induce emesis because of risk of serious corrosive injury. Whole bowel irrigation may be considered. Arrange for endoscopic examination if corrosive injury is suspected. 6.2 Supportive care Inhalation of mercury vapour Give supplemental oxygen and observe closely for several hours for development of acute pneumonitis and pulmonary oedema. Ingestion of mercuric salts Anticipate severe gastroenteritis and treat shock aggressively with IV fluid replacement. Treat renal failure supportively; it is usually reversible, but haemodialysis may be required for 1-2 weeks. Allergic reactions to dental amalgam Allergic reactions from dental amalgams usually respond to antihistmines. In patients unresponsive to antihistamine therapy removal of the fillings is recommended. 6.3 Monitoring With acute mercury vapour inhalation symptoms of pneumonitis may be delayed for several hours; a chest X-ray and arterial blood gases may show early signs of toxicity. Monitor electrolytes, fluid balance and renal function. Obtain blood and urine mercury levels. Collection of 24 hour urine mercury is useful in determining body burden. 6.4 Antidotes Chelation therapy should not be started until the gut has been emptied of mercury or it may enhance mercury absorption. For serious systemic intoxication DMPS (dimercaptopropanesulphonic acid) is the treatment of choice. It should be given IV in seriously ill patients and orally in those with less severe effects or in those with chronic mercury toxicity. Dosage - adults: Parenteral - slow injection over 3-5 minutes Day 1: 250mg IV every 3-4 hours, Day 2: 250mg every 4-6 hours, Day 3: 250mg every IV/IM every 6-8 hours, Day 4: 250mg every IV/IM every 8-12 hours. Following days: according to patient's clinical condition 250-750mg parenterally or change to oral medication. Children: Parenteral - slow injection over 3-5 minutes Day 1: 5mg/kg 6 times daily, Day 2: 5mg/kg 6 times daily, Day 3, 4, etc: 5mg/kg 1-3 times daily. Oral - acute poisoning Adults: 1.2-2.4g daily in divided doses (e.g. 12 times 100-200mg/24 hours). Children: 5mg/kg daily in divided doses. Oral - chronic poisoning Adults: 300-400mg/day in divided doses. The dose can be increased in severe poisoning. Children: 5mg/kg daily in divided doses. DMSA (succimer, 2-3 dimercaptosuccinic acid) has been used successfully as an oral chelating agent in a limited number of patients with mercury poisoning (Bluhm et al, 1992; Fournier et al, 1988; Graziano, 1986) and could be used in patients sensitive to DMPS. Dosage: Orally 30 mg/kg body weight daily for 5 days, then 20 mg/kg for 14 days. Dimercaprol (BAL) is another alternative. Dosage: 3-5 mg/kg IM every 4-6 hours for several days. Decisions on tapering the dose or ending the administration will depend on blood and 24-hour urine mercury concentration. After initial course of BAL, a oral chelating agent may be used. BAL injections are said to be painful. Penicillamine has also been used. Dosage: 100 mg/kg 24 hr (up to 1 g) in 4 divided doses. If treatment is to continue longer, the dose should be reduces to 35 mg/kg/24 hr. Animal experiments and some clinical experience indicate that N-acetyl-D, L-penicillamine (NAP) is more specific chelating agent for mercury. There is little human experience to support this finding. 6.5 Elimination techniques There is no role for dialysis, haemoperfusion, or repeat dose activated charcoal in mercury poisoning. However, dialysis may be required for supportive treatment of renal failure, and it may slightly enhance removal of the mercury-chelator complex in patients with renal failure. Haemodialysis clearance of the mercury-BAL complex is about 5 mL/minute (Atterbury and Olson, 1990). 6.6 Management controversies The use of dimercaprol (BAL) has been questioned in recent years with the advent of the less toxic hydrophilic BAL analogues DMSA and DMPS. Enhanced brain deposition may result from BAL treatment due to lipophilicity of the metal complex formed with dimercaprol. This has been described with inorganic arsenic and mercury. Experimental models using oral administration of mercuric mercury in mice showed that DMPS was superior to the other chelators in preventing mortality. Both DMSA and DMPS were superior to dimercaprol and NAP in alleviating acute toxicity, especially in the brain. Another study compared the potential to mobilise mercury and the incidence of drug induced toxicity of two chelating agents, DMSA and NAP (N-acetyl-D, L-penicillamine), after acute exposure to metallic mercury in man. DMSA was able to increase the excretion of mercury to a greater extent than NAP. In animal studies, DMSA was also shown to have greater activity than NAP in mobilising mercury from a toxic site (Houeto et al, 1994) A number of reports have indicated that in the treatment of acute mercury poisoning by dialysis little mercury is removed even with prior use of dimercaprol, except in the first few hours after exposure, therefore dialysis has usually been employed only in cases with renal failure. Other records, however, indicate then when potentially toxic doses have been taken, haemodialysis concurrent with dimercaprol administration may remove 10 to 15% of the ingested mercury and, even more importantly, relieve the kidneys and treat any uraemia caused by reversible kidney damage. Limited experience suggests an advantage of starting dialysis within the first 24 hr before maximal renal concentration can occur on the second day. This also may assist in controlling fluid and electrolyte imbalance as circulatory collapse accentuates the toxic tubular lesions (Aronow, 1990). 7 CASE DATA Case 1: Intentional ingestion - mercury salts A 17-year-old woman with psychological problems leading to four previous drug overdoses deliberately ingested a mouthful of mixed chemicals which she obtained as pure crystals from the laboratory where she worked. They were thought to comprise aniline hydrochloride and salts of barium, cadmium, lead, mercury, selenium and thallium in unknown proportions. She presented 7 hours later with vomiting and corrosive oral damage. Her face was flushed but there were no other abnormalities. She was treated with BAL and calcium disodium edetate, but became anuric within 16 hours. Her blood pressure remained normal. Haemodialysis was started at 24 hours in an attempt to remove chelated heavy metal. The results of the analysis taken during the first day of admission were available after 4 days and showed an extremely high mercury concentration in whole blood (1200 mg/L) measured by the cold vapour atomic absorption method. No other heavy metal was found at a concentration above normal. Calcium disodium edetate was therefore withdrawn, and BAL and dialysis was continued. The dose of BAL used was 100 mg IM 4 hourly during the first day, followed by 75 mg twice daily for the next 24 days. The patient then declined to accept the drug for 10 days, after which she was given 75 mg daily for a further 3 days. A renal biopsy showed severe tubular necrosis. She remained virtually anuric for 31 days and received a total of 180 hours dialysis during this period. Her renal function improved and the plasma mercury fell, dialysis became unnecessary, when the level had reached a concentration of approximately 100 mg/L. There were no other manifestations of mercury poisoning except for a mild normochromic anaemia and a transient elevation of her serum transaminase concentrations. Three months later her creatinine clearance was 56 ml/min (Newton et al, 1983). Case 2 and 3: Acute occupational inhalation - mercury vapour Two men, aged 35 and 50 years old weighing 75 and 108 kg, were exposed to mercury at work. They were jewellers and accidentally inhaled smoke containing mercury vapour produced during the melting of a gold block. The patients were exposed to the vapour for about half an hour. They presented with moderate headache, spreading pain, nausea, lumbar pain, gingival pain and shortness of breath at rest. The EEGs were characterised by slow alpha activity. The ECGs were normal. No CNS, EEG or nerve conduction velocity changes nor urological and cardiovascular symptoms were found. The patients had no evidence of any chronic respiratory disorder and arterial blood gas analysis was normal. Chelation therapy was given for 10 days. BAL was given initially (50 mg in the first injection, then 3 mg/kg 4 hourly for 2 days and then 3 mg/kg 6 hourly for 2 days). This was followed with oral DMSA (30 mg/kg), due to the painful nature of the intramuscular injections of BAL. Samples of plasma and urine were taken from the patients every 24 hour over a period of 10 days. The maximum plasma concentrations in the first sample were 239.5 mg/L and 93.3 mg/L in patient 1 and 2 respectively. They remained at a plateau of about 50 mg/L (patient 1) and 25 mg/L (patient 2). The serum creatinine and urea remained normal. In spite of the fact that high concentrations of mercury persisted in the plasma, no further symptoms were observed at any time in either patient during the 10 days BAL and DMSA were given. Observations were not made after the 10 day period (Houeto et al, 1994). Case 4: Chronic accidental inhalation - mercury vapour A 33 month old girl was admitted for anorexia, weight loss, light sensitivity and eczema, starting 4 months previously. She had widespread severely itching eczema and pink, sweating and scaling palms. She was ill-tempered and preferred to lie in bed or to be taken around in a small buggy. Acrodynia was suspected, and raised mercury concentrations was found in the urine. After 2 weeks of chelation therapy with DMPS (30 mg twice daily) the child's eczema and mood began to improve. After 4 months of therapy all symptoms had disappeared and mercury excretion was normal. Subsequently it was discovered that the mercury poisoning in this child was caused by mercury from a broken thermometer spilled on the carpet (Muhlendahl, 1990). Case 5: Accidental ingestion - mercuric chloride A 23 month old boy ingested an unknown quantity of mercuric chloride powder (a skin preparation) that he found on the lower shelf of a chemist's shop. Vomiting was induced (method not stated) and within 5 minutes his tongue and lips were seen to be swollen. On admission within an hour of ingestion the oedema and ulceration were so extensive that there was a risk of compromising the airway. However, a tracheostomy was not thought necessary. He was treated with dimercaprol 6mg/kg IM every 6 hours for 48 hours then half that dose for a further 48 hours. He was also given antibiotic cover and hydrocortisone. On admission the urea was 8.7mmol/L and creatinine 43µmol/L. The blood mercury level on admission was 4.5 mg/L (urine 30.4 mg/L). This had decreased to 0.95 mg/L (urine 8.5 mg/L) by the next day, 0.69 mg/L (urine 0.4 mg/L) on day 5 and 0.30 mg/L (urine 0.24 mg/L) by day 8. He suffered only mild renal impairment, this may have been due to prompt treatment. By day 8 he was able to swallow soft food without difficulty. He made a full recovery but the blood mercury level only returned to normal after more than 100 days (Stack et al, 1983). Case 6: Chronic dermal absorption - acrodynia A baby boy (2.15kg) developed nappy rash at the age of two weeks. The rash did not improve with cream prescribed by the family doctor and the mother began using Conotrane (hygraragaphen 0.05%). The baby became fretful and refused feeds. He began to vomit and his stools became watery. There was considerable erythema of the whole body with irritability, photophobia and watering of the eyes. Once it was discovered that the cream contained a mercury compound it was realised that he was suffering from acrodynia (pink disease). The urine mercury concentration was 120 µg/ml (Rajagopal and Hamilton, 1984). Case 7: Chronic accidental inhalation - mercury vapour A three year old boy was admitted to hospital with weight loss (2kg in 2 months) and acrodynia. A few days before admission he began to experience difficulty in walking. High mercury levels were found in the blood and urine. His parents and older and younger sisters all had elevated mercury levels. His two year old sister had been admitted to hospital 2 months earlier with a nephrotic syndrome of unknown cause. The only symptom in his 6 year sister was aesthenia. His parents were asymptomatic. According to the parents no mercury containing objects had been broken in the house. An ozone analyser was used to determine the source of the mercury. There was widespread contamination, with the highest concentration in hose of the vacuum cleaner and in the carpet of the children's room. Very high levels were found in the dust of the vacuum cleaner (3020 and 5984 µg/g of dust). Dust in the garage at ground level and the children's room at air level were 40 µg/g and 4.24 µg/m3 respectively. Extensive decontamination of the house was undertaken and 4 months later the mercury levels were decreased. All the family had at least one course of chelation therapy with DMSA and the clinical signs disappeared (Bonhomme et al, 1996). Case 8: Fatal accidental aspiration - metallic mercury A 48 year old man was admitted to hospital for reevaluation and treatment of Hodgkin's disease. Radiation therapy was begun on the retroperitoneal area and was well tolerated. However, during the sixth week of therapy he became unwell with nausea, vomiting, diarrhoea, fever, cramping and abdominal pain and abdominal distension. X-ray examination revealed distended, small bowel loops with multiple air-fluid levels. A Miller-Abbott tube was passed into the proximal ileum and 10ml of metallic mercury was placed in the bag. He began to improve over the following 4 days. The tube was then removed but the mercury bag ruptured while in the nasopharynx. The patient immediately began to cough and expectorated about 4ml of mercury. X-ray examination revealed considerable amounts of mercury in the stomach, duodenum and throughout the trachea, major bronchi and over both lung fields. An additional 5ml of mercury was removed by postural drainage, chest tapping and forced coughing. A repeat X-ray 3.5 hours later showed an increased amount of mercury in the left lung and a more diffuse alveolar spread in the right lung. The patient remained well for 12 hours, but then became pyrexial and irritable. By the next day he was incontinent of urine and faeces with weakness and abdominal pain. A mild cough produced small amounts of mercury-containing sputum. There was no mercury excretion in the 24 hour urine specimen. During the following 48 hours his temperature rose, he became confused and continued to complain of weakness and abdominal pain. A repeat urinary mercury determination was negative. He developed leucocytosis and albuminuria. Dimercaprol was started 72 hours after aspiration occurred. Four days after aspiration his symptoms persisted and he developed hypotension which responded to volume expansion. He developed an increasingly severe cough which produced bloody sputum. This was eventually produced in such large amounts that the airway could not be kept clear. He became tachypnoeic, cyanotic and comatose, and died 110 hours after aspiration of the mercury. During this time only 8.2ml of the mercury had been recovered. Permission for a postmortem was denied (Zimmerman, 1969). Case 9: Intentional ingestion - metallic mercury A 17 year male ingested approximately 205g (15ml) of metallic mercury and presented to hospital about 2 hours later. He was well on admission and a gastric lavage was performed. All investigations were normal. An X-ray 4 hours after ingestion showed mercury in the stomach and small intestine. By three weeks all the mercury had been passed in the faeces. He remained well and serial urine mercury levels were normal (all less than 15 µg) (Wright et al, 1980). Case 10: Chronic inhalation exposure plus acute intentional ingestion - metallic mercury A 42 year old man presented to hospital after ingesting approximately 3kg (220ml) of metallic mercury. He had worked since the age of 13 repairing thermometers, barometers, sphygomanometers and related instruments. In the last 2 years he had developed mild hand tremor, forgetfulness, fatigue and irritability. He was given a gastric lavage and cathartics. He complained of abdominal discomfort. An X-ray revealed mercury in the stomach and small intestine. By 2 weeks most of the mercury had passed in the faeces. An ophthalmological examination was normal. Neuropsychiatric and psychological evaluation revealed poor concentration and a defect in recent memory. An EEG showed diffuse cortical dysfunction. He was treated with penicillamine for 7 days. Blood and urine mercury levels 3 days after chelation therapy were 116.9 µg/L and 22.9 µg/L. Six months after ingestion he returned to hospital with mild jaundice and impaired liver function which resolved over the next 6 months (Lin and Lam, 1993). Case 11: Acute ingestion - button battery A two year old girl arrived in hospital within two hours of ingestion of a button battery containing mercury. The battery was visible on X-ray in the upper stomach. An X-ray the following day was unchanged but on the second day the battery was observed to be in two halves surrounded by radiopaque material. More radiopaque material was visible in the small bowel. The child remained asymptomatic. A gastrotomy was performed to remove the mercury salts from the stomach, areas of ulceration and bleeding were observed. The two halves of the battery casing were removed via an enterotomy from 60 cm beyond the pylorus. A blood mercury concentration at this time was 95 µL (normal <4 µg/L) and the urine mercury concentration 60 µg/L (normal <20 µg/L). Two days later the blood concentration was 230 µg/L and the urine 100 µg/L. Dimercaprol by IM injection was used as a chelating agent. Six days post-operatively the blood mercury concentration was 340 µg/L (urine 600 µg/L). At this time she had been vomiting intermittently but this became more persistent at nine days and an abdominal X-ray revealed small bowel obstruction. Radiopaque material was visible in the caecal region. A laparoptomy was performed and the obstruction was found to be due to adherence of the proximal jejunum to the abdominal wall. Multiple small ulcers were seen in the caecum. One week after the second operation no mercury was seen on X-ray and the blood mercury concentration was 25 µg/L. She was discharged and six weeks later the blood mercury concentration was down to 7 µg/L (Mant et al, 1987). Case 12: Acute fatal inhalation in a child- mercury vapour A 7 month old girl, her 3.5 year old brother and her father were admitted to hospital with a 12 history of fever, vomiting and dyspnoea. The family's six month old kitten had died the previous evening. Postmortem examination of the cat revealed diffuse pleural effusions and pneumonitis. The father and brother recovered over a 2-3 day period but the girl became increasingly dyspnoeic and was transferred to another hospital. On admission coarse breathing sound were heard bilaterally and heart sound were dull with a gallop rhythm. On the evening of the onset of effects the patient's father had been heating a metal thought to be lead on the kitchen stove. The kitten, brother and sister were all playing in the kitchen at the time. Black fumes were produced and the windows were opened. Analysis of the melted metal revealed it to be an amalgam of mercury and tin with smaller amounts of lead and zinc. The child was started in oxygen therapy but over the following three days the oxygen requirement was gradually increased. She had persistent metabolic acidosis and the pulmonary interstitial marking became more prominent. Blood mercury on the fourth day after exposure was 35 µg/L. Urine mercury excretion on the same day was 400 µg/24 hours, on the 5th day 130 µg/24 hours and on the 6th day 230 µg/24 hours. She was given methylprednisolone, sodium bicarbonate and penicillamine. On the 7th hospital day she developed increasing dynspnoea leading to apnoea. A chest X-ray revealed bilateral pneumonthorax with complete collapse of the right upper and left lower lobe. Despite adequate reexpansion, severe acidosis, coma and convulsions occurred and she died six hours later. At postmortem abnormalities were almost exclusively confined to the lungs. The mercury level in the brain was 2.9 µg/L, lung 5.2 µg/L, liver 5.1 µg/L and kidney 12.2 µg/L. In the family cat the level of mercury in the lung was 18 µg/L and in the kidney 12 µg/L (Moutinho et al, 1981). 8 ANALYSIS 8.1 Agent/toxin/metabolite Mercury can be measured in blood and urine. For inorganic and elemental mercury urine mercury determination is preferred. 8.2 Sample containers to be used Blood (10ml) in hard plastic or glass container with anticoagulant (heparin or EDTA). Urine (20ml) for random sample use sterile universal, for 24 hour sample collect in acid washed (nitric acid) hard plastic bottle. 8.3 Optimum storage conditions 8.4 Transport of samples 8.5 Interpretation of data Normal levels: Blood <10µg/L (<50nmol/L) Urine <20µg/L (<100nmol/L) Toxic levels: Blood >35µg/L (>175nmol/L) Urine >150µg/L (>750nmol/L) 8.6 Conversion factors Metallic mercury 1 mg3 = 0.12ppm 1µg/L = 4.985nmol/L 8.7 Other recommendations 9 OTHER TOXICOLOGICAL DATA 9.1 Carcinogenicity Inorganic mercury is generally not considered to be carcinogenic in humans (WHO, 1991). However, some data have suggested possible carcinogenicity of mercury in some occupationally exposed groups. 9.2 Genotoxicity WHO (1976) did not report any studies showing that inorganic mercury was genotoxic in humans. However, some data have since been reported suggesting possible genotoxic effects of inorganic mercury. 9.3 Mutagenicity DNA synthesis in animals exposed to mercury leads to the accumulation of the metal in the cell nuclei. The affinity of mercury for nuclear material was found to be considerable, binding largely to the chromatin. Mercuric chloride has been shown to cause depression of mouse leukaemic cells (Nakazawa et al, 1975). Reduction of DNA replication in Chinese hamster ovary cells has also been observed. Treatment of mice with mercuric chloride in vivo did not demonstrate an increased frequency of chromosomal aberrations in bone marrow cells or in spermatogonia (Poma et al, 1981). It seems likely that mercury poses a risk of mutagencity in heavily exposed individuals. 9.4 Reprotoxicity Six out of nine male workers accidentally exposed to mercury vapour (concentration 44.3 mg/m3 for less than 8 hours) developed acute mercury poisoning. During a follow up lasting several years they showed signs of chronic poisoning. A loss of libido which persisted for at least several years, was reported in all six cases. In a study carried out at a US Department of Energy plant that used very large quantities of metallic mercury, reproductive outcomes were studied among 247 male workers exposed to mercury vapour. No association was demonstrated between mercury exposure and decreased fertility, increased rates of major malformations of the offspring, or serious childhood diseases (WHO, 1991). There have been reports of menstrual disturbances in women exposed industrially or in dentistry to mercury vapour. A number of reports suggested that inorganic mercury compounds cause spontaneous abortion. During a 4 year period 17% of 168 exposed workers in a mercury ore smelting plant had experienced spontaneous abortion (average exposure 80 mg mercury/m3), compared with 5% among 178 controls. Toxaemia during pregnancy was reported in 35% of the exposed and 2% of the unexposed workers. On the other hand, De Rosis et al (1985), revealed no difference in the age standardised rate of spontaneous abortions between mercury exposed and unexposed females. Two other studies on female dental staff also reported no increased abortion rate when compared with age standardised controls. 9.5 Teratogenicity Studies on animals revealed that after brief exposure to elemental mercury vapour the mercury easily penetrates the placentar barrier (Greenwood et al, 1972). After equal exposure of pregnant rats, the foetal uptake was 10-40 times higher after exposure to mercury vapour than to mercury salts. In contrast, the placentar content of mercury after exposure to elemental mercury was only 40% of that after injected inorganic salts. The teratogenic effects of inorganic mercury has been investigated in the rat: increased resorption and abnormality rates were found, the malformations consisted of limbs and eye defects. Embryological, teratogenic and foetotoxic effects have also been demonstrated in the hamster; resorption rates were increased and growth retardation was seen in surviving foetuses. Malformations included: exencephaly, encephalocoele, anophthalmia, cleft lip and palate, rib fusions and syndactyly (Gale et al, 1982). Sikorski et al (1987) revealed a high frequency of malformations among dental staff. Of 117 pregnancies in the mercury exposed group, 28 pregnancies in 19 women led to reproductive failure, with spontaneous abortion (19 cases) and stillbirth (3 cases) and congenital malformations (5 cases of spina bifida and one case of intra-atrial defect). In non exposed controls, there were 7 cases of adverse pregnancy outcome in five women out of a total 63 pregnancies (30 women). Another study investigated the Swedish National registers for birth records. There was no tendency towards an elevated rate of malformations, abortions or stillbirth among dentists dental nurses and dental technicians. On balance it would seem likely that there is risk of teratogenicity or foetal toxicity following maternal exposure to mercury vapour or inorganic salts. 9.6 Acceptable daily intake (ADI) The Food and Agriculture Organisation WHO Expert Committee allocated a provisional tolerable weekly intake for adults of 0.3 mg/person or 0.005 mg/kg. 9.7 AOEL In the UK the occupational exposure standards of mercury and mercury compounds (except mercury alkyls) are 0.05 mg (as Hg) per m3 long term and 0.15 mg (as Hg) per m3 short term. In the USA the permissible and recommended exposure limits for inorganic mercury are 0.1 mg/m3 (maximum long term) and 0.05 mg/m3 (long term). 9.8 Relevant animal data Evidence of damage to brain, kidney, heart and lungs in rabbits exposed acutely to metallic mercury vapour at a concentration of 29 mg/m3 have been reported. The LD50 for inorganic mercury lies between 10 and 40 mg/kg body weight for all compounds tested. For mercuric chloride, a value of about 10 mg/kg body weight has been observed after parenteral administration to mice. The features of acute toxicity usually consisted of shock, cardiovascular collapse, acute renal failure and severe gastrointestinal damage (WHO, 1991). WHO (1976) in evaluating a number of experimental studies on animals, concluded that both reversible and irreversible effects may be caused by mercury and its compounds. Microscopically detectable changes have been seen in the organs of dogs, rabbits and rats exposed to concentrations of mercury vapour ranging from about 100 to 30 000 mg/m3 for different period of time. Severe damage was noted in kidneys and brains at mercury concentration of about 900 mg/m3 after an exposure period of about 12 weeks. After exposure of dogs to 100 mg mercury/m3 for 7 days, 5 days /week, over a period of 83 weeks, no microscopically detectable effects were seen, and tests revealed no abnormalities in the kidney function. In two studies tremor and behavioural effects were observed in rabbits and rats after several weeks exposure to mercury vapour at levels of several mg/m3, although there were no morphological changes in the brain. During the last 10-20 years, great attention has been paid to effects of inorganic mercury on the immune system. A number of studies have been evaluated and it is concluded that depending on the animal strain tested, either auto-immunity or immunosupression may be observed (WHO, 1991). Selenium has been found to affect the distribution of mercuric mercury in many animal species. As a consequence of this redistribution decreased toxicity has also been observed. Mercury forms a mercury-selenium protein complex with selenium. This complex can be identified in plasma and blood cells. Given together with selenium, mercury is retained longer in the blood, and as a consequence lessens accumulation in the kidney. The mercury taken up by the kidney is bound to the protein-selenium complex, binding to metallothionein is diminished or negligible on administration of equivalent amounts of selenium. Studies of selenium interaction with mercury have mainly been done on animals. Selenium metabolism in man is different from that in most animals. Observations in workers exposed to mercury vapour indicate, however, that there is a remarkable relationship between selenium concentrations and mercury concentrations in organs such as brain, thyroid and pituitary. Transport of mercury over the placental membranes is also inhibited (Berlin, 1986). 9.9 Relevant in vitro data Mercuric chloride has been shown to cause depression of mouse leukaemic cells (Nakazawa et al, 1975). Reduction of DNA replication in Chinese hamster ovary cells has also been established. Treatment of mice with mercuric chloride in vivo did not demonstrate an increased frequency of chromosomal aberrations in bone marrow cells or in the spermatogonia (Poma et al, 1981). 10. ENVIRONMENTAL DATA 10.1 Ecotoxicological data Solubility in water Elemental mercury: approximately 60 mg Hg/L at 24°C. Volatilisation Metallic mercury is rather volatile. A saturated atmosphere of mercuric vapour contains approximately 18 mg Hg/m3 at 24°C. LC50 The 96 hour LC50 varies between 33 and 400 mg/L for freshwater fish and are higher for seawater fish. 10.2 Behaviour Adsorption onto soil In an experimentally set-up, the pH and chloride concentration in soils was changed and the effect on the sorption of mercury determined. With no chloride there was only a small effect of pH between 4 and 6; sorption decreased at higher pH. Addition of chloride had minimal effect at higher pH and decreased sorption at low pH. Between pH 4 and 5.8, the effect of mercury sorption was entirely due to changes in the HgOH+ concentration in solution. Heavy metals were found in 2 to 5 fold higher concentrations near roadside soils than in soils some distance removed from the road. The typical roadside concentration of mercury was 0.12 mg/kg of soil (Poisindex, 1995). 10.3 Biodegradation Environmental fate Mercury vapour is converted to soluble forms and deposited by rain into soil and water. The atmospheric residence time for mercury vapour is up to 3 years, where soluble forms have a residence time of only a few weeks. The change in specification of mercury from inorganic to methylated forms is the first step in the aquatic biotransformation process. This can occur non-enzymatically or through microbial action (WHO, 1991). Abiotic transformation The change in specification of mercury from inorganic to methylated forms is the first step in the aquatic biotransformation process. Experiments performed without the presence of any bacteria showed that transfer of methyl groups occurs non-enzymatically. Aerobic/anaerobic It has been shown that cell extracts of a strictly anaerobic methanogenic bacterium effectively converted inorganic mercury into methylmercury . Microbial About 37 consortia were isolated in the presence of mercury chloride. These strains retained between 82 and 90% of the total mercury influent in fixed bed experiments. The retention mechanism was the reduction in ionic mercury to metallic mercury (Poisindex, 1995). Half-life in water, soil and vegetation Water: The half-life of mercury can vary considerably, depending on whether biological and non-biological mechanisms are involved. Artificial decontamination of bottom sediments has cleaned up Minimata Bay and the nearby Yatsushiro Sea, to a large extend accelerating the natural process by an estimated 31.5 years. The natural decontamination of the Yatsushiro Sea is estimated to have a half-life of 9.5 years. The decontamination of the Ottawa River, where only natural processes were involved, was found to have a half-life of 1.5 years. Vegetation: Low levels of uptake of inorganic mercury from the soil by plants have been reported. 10.4 Environmentally important metabolites The change in specification of mercury from inorganic to methylated forms is the first step in the aquatic biotransformation process. This can occur non-enzymatically or through microbial action (WHO, 1991). 10.5 Hazard warnings Aquatic life Fish take up metallic mercury and retain it in the tissues, principally as methylmercury, although most of the environmental mercury to which they are exposed is inorganic. The source of methylation is uncertain, but there is strong indication that bacterial action leads to methylation in aquatic systems. Elimination time is slow in fish (with half lives in the order of months or years) and from other aquatic organisms (WHO, 1991). 10.5.1 Bees No data available. 10.5.2 Birds Sea birds and those feeding in estuaries are most at risk of mercury poisoning. The form of retained mercury is variable and depends on the species, organ and geographical site. 10.5.3 Mammals Bioaccumulation: An experimental study was carried out with six sheep which were given 4 mg inorganic mercury in their feed for 28 days. The results suggest that the long term ingestion of mercury leads to a chronic effect on the production of farm animals. High tissues concentrations of mercury have been found in a number of wild animals. 10.5.4 Plants Barley was used to assess plant-availability, tissue concentration and genotoxicity of mercury from the solid waste deposited of a chloralkali plant. Roots were found to take up most of the mercury, bioconcentration in the straw was minimal and accumulation of mercury in the grain did not increase with increased mercury in the soil, indicating a restriction of transport function (Poisindex, 1995). 10.5.6 Protected species Inorganic mercury is toxic to micro-organisms, aquatic life, insects, birds and mammals, therefore, a number of protected species would be at risk if exposed to toxic doses. High tissues concentrations of mercury have been found in a number of wild animals. 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