REVIEW Toxicity of Mercury
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Journal of Human Hypertension (1999) 13, 651–656 1999 Stockton Press. All rights reserved 0950-9240/99 $15.00 http://www.stockton-press.co.uk/jhh REVIEW Toxicity of mercury NJ Langford and RE Ferner West Midlands Centre for Adverse Drug Reaction Reporting, City Hospital, Dudley Road, Birmingham B18 7QH, UK A ruling by the European Union heralds the demise of poisoning can occur if mercury metal is spilled into those useful clinical instruments, the mercury ther- crevices or cracks in the floorboards. Dentists are mometer and the mercury sphygmomanometer. The occasionally poisoned this way. Mercury easily crosses new laws have been passed because of worries about into the brain, and causes tremor, depression, and mercury poisoning. Yet you can drink metallic mercury behavioural disturbances. A second danger from met- and come to no harm. What does it all mean? There are allic mercury is that it is biotransformed into organic three forms of mercury from a toxicological point of mercury, by bacteria at the bottom of lakes. This can be view: inorganic mercury salts; organic mercury com- passed along the food chain and eventually to man. It pounds; and metallic mercury. Inorganic mercury salts was this process that led to the Japanese tragedy at are water soluble, irritate the gut, and cause severe kid- Minimata Bay in the late 1950s when over 800 people ney damage. Organic mercury compounds, which are were poisoned. It is the need to reduce mercury con- fat soluble, can cross the blood brain barrier and cause tamination of the environment which should encourage neurological damage. Mercury metal poses two dan- us to cut the usage of metallic mercury. However, much gers. It can be vaporised: the vapour pressure at room more metallic mercury is spilled as waste by the chemi- temperature is about 100 times the safe amount, so cal industry than is dropped on the floor in the clinic. Keywords: mercury; toxicity; thermometer; sphygmomanometer Toxicity of mercury and organometallic mercury compounds and we review each form separately. A new European Union directive1 will prohibit the use of mercury in sphygmomanometers and clinical thermometers. We review here the toxic effect of Metallic mercury mercury and its compounds and discuss their rel- Metallic mercury (liquid mercury, quicksilver, evance to the environment and to modern medicine. hydrargyrum (hence Hg), elemental mercury), is a The Chinese used mercury (II) sulphide 1000 silver white metal which melts at −38.7°C. Mercury years before the birth of Christ as the red dye pig- is best known as a liquid metal, having a vapour ment vermilion. It was used similarly in the Graeco- pressure (a measure of the amount of vapour ‘given Roman world, with both Hippocrates and Galen rec- off’) of 0.002 mm Hg at 25°C. This approximately ording its toxic effects. Since then its toxicity has doubles for every 10°C increase in temperature, so become well known in metalworkers, miners, felt- that heating metallic mercury greatly increases the hat manufacturers, dyers and paint manufacturers. associated risks, as inhalation is the usual route of Despite this, mercury has been incorporated into the toxicity. Inhaled mercury vapour accumulates in the treatment of man’s maladies from ancient times. Its body, and in particular the central nervous system, main use has been to treat syphilis, from its first which is the site of its major toxic actions. Orally appearance in the West in the 15th century up to ingested elemental mercury rarely causes acute toxic World War II.2 Mercury and its salts have at various effects, as gastro-intestinal absorption is low—less times been used as antiseptics, skin ointments, laxa- than 0.01% of the dose.3 For practical purposes, tives, diuretics, bowel washouts for the treatment of ingestion of oral elemental mercury as a single dose colorectal cancer, and scabicides. It is still used poses a negligible risk of severe toxicity. The oral today as a solvent for the silver-tin amalgams used LD10 is reported to be 1429 mg/kg (in man), or in dental fillings. So how toxic is mercury? approximately 100 g for a 70 kg adult. Percutaneous absorption is also low (approximately 2% of the rate The hazards of mercury of uptake by the lung).4 There are substantial differences in toxicity of Absorption by inhalation readily occurs, as mer- 5 elemental mercury metal, inorganic mercury salts, cury vapour freely crosses the alveolar membrane with nearly 100% bioavailability.6 Once absorbed, a proportion of mercury is taken up by the red blood Correspondence: NJ Langford, West Midlands Centre for Adverse cell, whilst some remains in the bloodstream, Drug Reaction Reporting, City Hospital, Dudley Road, Birmingham. B18 7QH, UK allowing its rapid distribution around the body, Received 10 March 1999; revised 28 May 1999; accepted 10 including the central nervous system. Within the June 1999 red blood cells, liver, and central nervous system the Toxicity of mercury NJ Langford and RE Ferner 652 metal is oxidised via the catalase-peroxide pathway browns and blacks of the sulphide compounds. to mercury (II) oxide. The rate at which this reaction They are also commonly used in industry. They occurs is limited in the presence of catalase inhibi- have been used in medicine in teething powders, tors and competitive substrates such as ethanol. skin-lightening creams and as preservatives in cer- Mercury excretion from the body starts almost tain medicines—particularly as eyedrops. Mercury immediately after absorption, following a variety of (I) chloride (calomel) was widely used as a purgative routes, though principally by the kidneys.7 Minor in the form of the ‘blue pill’. routes of excretion include the gastro-intestinal tract The toxicity of mercury salts varies with their and saliva into which mercury is actively secreted, solubility. Usually mercury (I) compounds are of as well as from the lungs, in the nails and the hair low solubility and significantly less toxic than mer- and also from sweat glands. There is a relatively fast cury (II) compounds. Inorganic mercury salts initial phase, during which a third of the inhaled present a far greater hazard than elemental mercury mercury is rapidly concentrated in the liver and kid- if ingested orally, owing to their greater water solu- neys, and excreted in the bile or urine. This phase bility.17 For mercury (II) chloride, the lethal dose has an estimated half-life of 2–16 days. A still slower may be as small as 0.5 g, compared with 100 g mer- second phase, reliant on renal accumulation and cury metal. Mercury salts are usually non-volatile probably responsible for the excretion of the solids, so poisoning by inhalation is rare, though majority of the body’s mercury load via the urine, toxicity may arise if aerosols are deposited in the has a half-life of 30–60 days.8 A slower third phase lungs. Once adsorbed, the mercury (I) form will of excretion, via the kidney, has been postulated readily react with the thiol groups of amino acids accounting for ෂ15% of the mercury load.9 Mercury such as cysteine. The protein metallothionein, func- deposited within the brain has an elimination half- tions as a natural chelator, preventing damage by 10 life that may exceed several years. In workers with mercury and other transitional metals to thiol- high lifetime exposure to elemental mercury, containing proteins. Once metallothionein proteins deposits of mercury were found in the brain at auto- are saturated, other structurally related proteins can psy, even though exposure to mercury had ceased be damaged. Inorganic mercury salts are not lipid 11 years previously. In rats, the highest concen- soluble, and so do not cross the blood brain barrier trations of mercury were found in the Purkinje cells in significant amounts. The majority of the dose of of the cerebellum and in certain neurons of the spi- 12 an ingested inorganic mercury salt accumulates nal cord and midbrain. either in the liver, where it is excreted in the bile, The toxicity of mercury vapour is dose-depen- or in the kidney, where it is excreted in the urine. dent. Exposed patients may initially complain of a The symptoms and signs of inorganic mercury metallic taste. Three to 5 h after a high acute poisoning arise in two phases. Very soon after inges- exposure, cough, dyspnoea, chest tightness, leth- tion, there is burning pain in the chest, rapid dis- argy, restlessness, fever and signs of pneumonitis colouration of the mucous membranes (secondary to can develop. If the exposure levels are sufficient, precipitation of proteins in the mucosal lining), and and especially when accumulation occurs after gastro-intestinal pain from direct local trauma due repeated exposures, then central nervous symptoms to the salts’ corrosive nature. There can be vomiting and signs arise, with tremor, and erethism (behavioural disturbances).13 Vasomotor disturb- and a profuse bloody diarrhoea which can in ances may also occur with excess perspiration and extreme cases lead to hypovolaemic shock and blushing. Other oral changes include ulceration, death. If the patient survives the initial effects of the bleeding gums and loosening of the teeth.14 poison, the systemic effects predominate, with mer- Chronic poisoning markedly affects the central curial stomatitis (glossitis, ulcerative ginigivitis, nervous system and kidney. Tremor, initially hypersalivation, and a metallic taste), loosening of involving facial muscles and eyelids, is present at the teeth, and renal damage. The renal damage arises rest, but aggravated by intention. It gradually secondary to accumulation of the mercury salt in the becomes more pronounced and also starts to affect proximal convoluted tubules, causing a transient the limbs. Handwriting becomes illegible, with polyuria, proteinuria (in severe cases a nephrotic omission of letters and eventually whole words; syndrome), haematuria, anuria and renal acidosis.