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Mercury and mercurial salts
Mercury and mercurial salts 10. Wenner WJ, Murphy JL. The effects of cysteamine on the upper gastrointestinal tract of children with cystinosis. Pediatr Nephrol 1997;11(5):600–3. 11. Landers MC, Law S, Storrs FJ. Permanent-wave dermatitis: contact allergy to cysteamine hydrochloride. Am J Contact Dermat 2003;14(3):157–60.
Mercury and mercurial salts General Information Mercury is a silver-colored metallic element in fluid form (symbol Hg; atomic no. 80). Its symbol derives from the Greek name for the element hydrargyros. It is found as the sulfide salt in cinnabar, the source of the pigment vermilion. With a few exceptions, the use of metallic mercury in medicine is considered to be outdated; the few exceptions include its use in certain preservatives and in dental amalgam. The radioactive nuclides 197Hg and 203Hg have been used diagnostically, but the amount of mercury involved is very small. Even the mercury thermometer is rapidly being replaced by safer alternative devices. The use of mercury in dermatological therapy should be abandoned because of the risk of mercury intoxication (1). Aryl mercurials that have been used medicinally include phenylmercuric acetate, phenylmercuric nitrate, nitromersol, thiomersal, merbromin (mercurochrome), and mercurobutol. These compounds are variously used as preservatives in drugs, including vaccines, for skin disinfestation, the treatment of infections of the skin and mucosa, and in contraceptive jellies and hemorrhoidal remedies; they have also been used in some cosmetics. The aryl mercurials are better absorbed across the mucous membranes than most inorganic mercury salts. Regrettably, some therapeutic exposure to mercury continues, more particularly generally outside the Western world. Non-prescription laxatives containing mercurial compounds are still sold in some countries. The presence of mercury may not always be divulged on the label. Mercury poisoning can also occur through consumption of fish that have swum in waters that have been contaminated with methyl mercury from industrial waste (Minamata disease) (2). When it was first described, in May 1956, the marine products in Minamata Bay contained high concentrations of mercury (6–36 ppm). Mercury was also found in the hair of patients, their families, and the inhabitants of the Shiranui Sea coastline (maximum 705 ppm). Typical symptoms include sensory disturbances (glove and stocking type), ataxia, dysarthria, constriction of the visual fields, auditory disturbances, and tremor. Mercury poisoning has also been seen in the children of mothers who have eaten contaminated marine life (congenital Minamata disease). Acute and chronic mercury poisoning The characteristic clinical picture of acute mercury poisoning includes sudden profound circulatory collapse with tachycardia, hypotension and peripheral vasoconstriction, ª 2006 Elsevier B.V. All rights reserved.
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vomiting, and bloody diarrhea due to hemorrhagic colitis. Renal insufficiency usually develops within 24 hours and is associated with albuminuria, epithelial cell casts, and red cells in the urine, glycosuria, and aminoaciduria. Oliguria can proceed to complete anuric failure. There is also neutrophilic leukocytosis due to tissue necrosis (SED-11, 483) (3). Symptoms of chronic mercury poisoning have been reviewed (4–6). The symptoms are listed in Table 1. The urinary tract is very sensitive to poisoning by all forms of mercury, a sensitive indicator of early injury being a rise in the urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG) (7). In 70 patients with psoriasis treated with an ointment containing ammoniated mercury, symptoms and signs of mercury poisoning were detected in 33 (8): albuminuria, headache, gingivitis, erythroderma, nausea, dizziness, precordial pain, contact dermatitis, conjunctivitis, epistaxis, keratitis, tremor, neuritis, hematological changes, metallic taste in mouth, and purpura. Acrodynia (‘‘pink disease’’) is thought to be a particular form of mercury hypersensitivity, which can be caused by organic or inorganic mercury; it formerly occurred in young children exposed to teething formulations containing mercury compounds. Typical signs include pink scaling palms and soles, flushed cheeks, pruritus, photophobia, profuse irritability, and insomnia. A modern case of acrodynia involved a patient with congenital agammaglobulinemia who had received merthiolate-containing gammaglobulin injections for 15 years (SEDA-6, 225). Mercury poisoning has been reported in a child who took a Chinese herbal medicine (9).
A 5-year-old Chinese boy developed oral ulceration, mainly affecting the left lateral aspect of his tongue, and 5 weeks later motor and vocal tics. Herpetic ulceration was diagnosed and confirmed by the isolation of
Table 1 The symptoms of chronic mercury poisoning System
Symptom
Cardiovascular Nervous system
Hypertension, hypotension Emotional disturbances, irritability, hypochondria, psychosis, impaired memory, insomnia, tremor, dysarthria, involuntary movements, vertigo, polyneuropathy, paresthesia, headache Corneal opacities and ulcers, conjunctivitis, hypacusis Hyperthyroidism Hypochromic anemia, erythrocytosis, lymphocytosis, neutropenia, aplastic anemia Loose teeth, discoloration of the gums and oral mucosa, mouth ulcers, fetor Anorexia, nausea, vomiting, epigastric pain, diarrhea, constipation Nephrotic syndrome Tylotic eczema, dry skin, skin ulcers, erythroderma Acrodynia, arthritis in the legs Dysmenorrhea
Sensory systems Endocrine Hematologic
Mouth Gastrointestinal Urinary tract Skin Musculoskeletal Reproductive system
2260 Mercury and mercurial salts Herpes simplex virus type 1 from a tongue swab. The lesion improved with oral aciclovir (200 mg five times a day for 5 days), but relapsed a few days later. A local pharmacist prescribed a Chinese medicinal herb mouth spray called ‘‘Watermelon Frost’’, said to be useful in controlling pain and healing difficult mucosal wounds. Over the following weeks his oral symptoms improved but he became irritable and cleared his throat frequently. He developed a transient skin rash on his trunk and motor tics (eye blinking, head turning, and shoulder shrugging). His blood lead concentrations was 0.31 mmol/l (normal below 1.5) and his blood manganese concentration was 246 nmol/l (normal 70–280); his urine arsenic concentration was 10 nmol/mmol creatinine (normal <68). His blood mercury concentration was 83 nmol/l (normal for adults <50). The mercury content of the spray was 878 ppm (2% methyl mercury and 98% inorganic mercury). There was a significant difference in mercury content between different brands and between batches of the same brand of the Chinese medicinal herb. The spray was withdrawn and his tics completely resolved within 4 weeks.
exposed to particularly high levels of mercury. This finding has led to a widespread belief in some countries, supported by certain scientific workers (16), that mercury released from amalgam may be the cause of some hitherto unexplained diseases, and a demand has arisen for the removal of amalgam fillings. A number of case histories have been published of individuals in whom chronic (primarily neurological) disorders appear to have responded to removal of amalgam. Although it is acknowledged that occasional individuals are allergic to metallic mercury, the view that it presents any other risk has generally been contested by the dental profession, citing evidence that the mercury released from amalgam will not accumulate in the body as long as there is adequate renal function. A meta-analysis has shown numerous logical and methodological errors in the antiamalgam literature (17). The author concluded that the evidence supporting the safety of amalgam is compelling. The debate continues (18,19). There have been reports of allergic reactions to dental amalgam.
Metallic mercury Metallic mercury (SEDA-21, 239) is poisonous, and prolonged or acute inhalation can be fatal; organic damage results in a severe chemical pneumonitis. Gingivitis, sometimes proceeding to loss of the teeth, is a wellrecognized consequence of prolonged low-level exposure to the metal. Inhalation of vapor from broken thermometers by persons allergic to mercury or even skin exposure can give rise to allergic contact dermatitis (10). If the liquid metal enters the system, even a small amount can cause complications (SEDA-22, 248), although much of the metal is likely to remain at the site of entry and some will be trapped by the lymphatic system. In one remarkable case, a nurse accidentally pierced her hand with a broken mercury thermometer, and developed amyotrophic lateral sclerosis 3 years later; the causal link was uncertain but there was some reason to believe that the metal had activated a latent predisposition to the disorder (11).
A man who attempted suicide by injecting 40 ml mercury was found to have mercury deposits at the injection site and in the lungs (12). A man who injected mercury intravenously developed malaise and weight loss, and a bilateral cervical adenopathy was found (13).
Dental amalgam Dental amalgam (SEDA-10, 210) (SEDA-15, 233) (14,15) is still used for about 75–80% of single-tooth restorations. The modern amalgam consists of a metallic alloy (silver, tin, and copper, sometimes with small amounts of zinc, indium, and/or palladium) mixed with mercury in a percentage of 40–54% mercury by weight. The resultant plastic mass sets and hardens over a period of 8–24 hours. Contrary to previous belief, measurable amounts of mercury escape from dental amalgam fillings in the form of vapor, ions, and abraded particles, and individuals who are accustomed to chew their food thoroughly are ª 2006 Elsevier B.V. All rights reserved.
A 32-year-old dentist had multiple exudative erythematous pruritic plaques on his limbs and trunk for 3 years (20). Although the eruptions were seen almost throughout the year, his symptoms tended to be worse in the summer. Topical corticosteroids, white petrolatum, and oral antihistamines had given slight relief, and an oral corticosteroid gave him transient relief from the itchy eruptions. Patch tests showed that he reacted to 1% ammoniated mercuric chloride in petrolatum and to 0.05% mercuric chloride in water. It was suggested that his dental amalgam should be removed and that he avoid contact with amalgam during his work. Two weeks later his skin symptoms had dramatically improved, leaving pigmentation. Thereafter he was free of symptoms for several months. However, when he handled amalgam again, similar but less severe eruptions appeared on his legs the next day. Subsequent strict avoidance of amalgam improved his eruptions. A 70-year-old man had multiple coin-sized exudative eczematous plaques on his legs and trunk for several months (20). Various kinds of corticosteroid ointments and white petrolatum as an emollient gave him little relief. Patch tests showed that he reacted to 1% ammoniated mercuric chloride in petrolatum and 0.05% mercuric chloride in water. He had all his dental amalgam removed, and 1 month later his eruption had subsided, leaving pigmentation. A 50-year-old man complained of soreness of the left buccal mucosa and the right side of his tongue, made worse by consuming spicy foods and acidic drinks (21). He had a heavily restored dentition, with asymmetrically distributed white striated and red atrophic lesions on the left buccal mucosa and the right and left borders of the tongue. The lesions were in direct contact with the buccal and palatal surfaces of an old corroding and amalgam restoration and the lingual surface of an amalgam restoration. A provisional diagnosis of a lichenoid reaction to amalgam was made and patch tests showed a strong positive response to mercury and a slightly weaker response to amalgam after 72 hours. One amalgam filling was covered with a bonded porcelain crown
Mercury and mercurial salts
and the other was replaced with glass ionomer cement. Within 2 months he was asymptomatic, and after 12 months the lichenoid lesions had completely resolved. A-57-year-old woman (21) had a recurrent urticarial rash on the skin of her face, scalp, and neck precipitated by restorative dental treatment. The reactions were fully established within 12 hours and would resolve over 2–3 days and be completely gone within 1 week. Patch tests showed a strong reaction to mercury. She was advised that alternative dental materials should be used and that existing amalgam should be removed.
Organic salts Organomercurials have been a common cause of allergic contact dermatitis or rash (22) and even exfoliative dermatitis has been described (23). Some reagents for intracutaneous testing (tuberculin, etc.) may contain thiomersal, which can cause sensitization and thus elicit false-positive delayed-type skin reactions. Mercury compounds inhibit most lymphocyte functions (SEDA-21, 240). An early indicator of an immunological response to mercury exposure, for example in occupational medicine, appears to be a change in the lymphocyte count with a differential increase in T helper cells and a rise in the T helper/T suppressor ratio (24). Merbromin Merbromin (mercurochrome, the disodium salt of 2,7dibromo-4-hydroxymercurifluorescein) is the oldest organic mercurial antiseptic in use, but it is active only as a bacteriostatic agent. In contrast to earlier assumptions, it is absorbed through burned or otherwise absorptive surfaces, and can cause severe and lethal intoxication. High mercury concentrations in blood, urine, and organs have been demonstrated (SED-11, 483). Young children run a particular risk of renal damage from absorption of organic mercury compounds used as antiseptics; in one case, frequent application of merbromin to an omphalocele apparently resulted in anuria, respiratory arrest, and death (SED-8, 520). Neither merbromin nor thiomersal can be considered useful in the management of large omphaloceles.
A patient developed mercury intoxication, including aplastic anemia, after local application of merbromin to an operation wound (SED-11, 483) (25). A 37-year-old patient with burns involving 50% of the body surface was treated by Grob’s three-phase method (2% merbromin, 5% tannic acid, and 10% silver nitrate solutions) (26). By day 6 he had pink-coloured urine and progressively developed restlessness, confusion, and coma, with hypothermia on day 8. He died on day 10 with respiratory arrest. The mercury concentration of the urine was 2170 ng/ml on day 6 and 1250 ng/ml on day 9.
The authors pointed out that merbromin should no longer be used in the treatment of burns. However, good results were reported in a retrospective study on the treatment of second-degree burns in 129 children using the same method (solutions with 7% silver nitrate and 2% merbromin). The authors pointed out that the indication is given only in second-degree burns, with burned surfaces of ª 2006 Elsevier B.V. All rights reserved.
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maximally 10–20% of the body surface, preferably in burn injuries of the trunk and non-mobile areas of the extremities. The most important factor seems to be careful attention to the serum sodium concentration and sufficient substitution with infusion therapy (SED-11, 483). An anaphylactic reaction occurred after local application of merbromin in one patient, and several mercurysensitive patients had severe local reactions in patch tests (SED-11, 483) (27).
Thiomersal Thiomersal (O-ethylmercurithiobenzoic acid), an organic mercurial, was first added to childhood vaccines as a preservative in the 1930s. It contains 50% ethyl mercury by weight. It was the potential for infants to be exposed to cumulative doses of mercury from thiomersal in vaccines that prompted the European Medicines Evaluation Agency and the UK’s Committee on Safety of Medicines (CSM) to recommend that it would be prudent to promote the use of vaccines without thiomersal as a precautionary measure (SEDA-26, 259). Thiomersal is also widely used in cutaneous test solutions and in contact lens cleaners and creams. The danger of toxic effects and the efficacy of thiomersal are similar to those of merbromin. Toxic amounts can be absorbed during omphalocele treatment. The aryl mercurials, such as thiomersal are particularly likely to elicit hypersensitivity reactions (10,28), including attacks of asthma in patients who have received hepatitis B vaccine (29). Ethyl mercury toxicity and sensitization from thiomersal-containing vaccines have been indecisively discussed (30,31). The toxicity of ethyl mercury has also been discussed (32). Fatal mercury (and borate) intoxication has been reported after irrigation of the ear with 0.1% thiomersal and 0.14% sodium borate for purulent otitis media, which was refractory to antibiotic therapy over 4 weeks (SED11, 483) (33). The histories of 25 patients with chemical burns caused by preoperative skin preparation have been reviewed. Thiomersal was the most common agent implicated. The burns did not occur in the main area of preparation, but more peripherally where the solution was in close contact with the skin in the drapes or was more closely applied to the skin by pressure, either because of the patient’s own weight or to tourniquet dressings. No burning occurred under a sterile wound drape (although solutions stagnate at this site and do not evaporate), perhaps because there was no pressure. There are particular risks in patients placed in the lithotomy position to undergo gynecological operations (the burns being on the buttocks), and in those undergoing orthopedic operations (the burns then being on the extremities and under a tourniquet) (SED-11, 483) (34). Thiomersal is one of the most frequent sensitizers in the world (3,35). It is used as a preservative in vaccines, test solutions, and topically administered applications, for example creams and solutions used on eczematous skin, ear-drops, eye-drops, and cleanser solutions for ocular contact lenses. The concentration of thiomersal varies between 0.0005 and 0.01% in these formulations. Sensitization can be provoked by immunization with thiomersal-containing vaccines. Even in sensitized
2262 Mercury and mercurial salts patients, thiomersal-induced adverse effects due to immunization has not been shown to be a severe risk, and a positive patch test to thiomersal does not represent a contraindication to immunization with thiomersalcontaining vaccines. Many of the reactions seen in patch tests with 0.1% thiomersal are probably caused by the irritant nature of thiomersal. It has been pointed out that only half of a series of subjects tested with a solution of 0.1% thiomersal had a positive reaction in patch tests with concentrations of 0.05 and 0.01% (36). Thiomersal included in patch-test series has given varying frequencies of positive reactions. Cross-reactions occur to a few organic mercurials, but not to inorganic or metallic mercury. The allergic determinant seems to be the ethyl mercury radical in thiomersal. Frequencies of positive reactions have been reported in the following countries:
USA: 13.4% in 1967 (37) and 8% in 1972 (38) Japan: 5.6 (39) and 16.3% (40) Finland: 2.0% (41) Denmark: 1.3% (42) GDR: 6.9% (43) Czechoslovakia: 5.3% in infant inpatients (44) France and Belgium: 2.3% in a multicenter study in 200 adult patients submitted to routine patch-testing (45) Italy: 5.3% (46) Poland: 5.7% (13.8% of all medicinal personnel, tested in this study) (47).
There was a very high peak frequency of positive patch tests in the 20–30 years age group in Sweden (48): 16% of male recruits and 10% of other healthy subjects in nursing schools and among medical students. A common reason for sensitization to thiomersal in the younger generation in Sweden arises from intracutaneous testing with tuberculin containing thiomersal as a preservative. It was shown experimentally that tuberculin could act as adjuvant during sensitization to thiomersal. The iatrogenic occurrence of thiomersal allergy in the Swedish population does not result in eczematous reactions, but merely in false-positive skin tests. Thiomersal takes second place, after nickel, as a contact allergen in Austria. As in Sweden this high incidence is probably due also to frequent immunization with vaccines containing thiomersal (49).
A generalized allergic reaction occurred in a 50-yearold nurse with a documented allergy to thiomersal, who received 10 ml of human euglobulin with thiomersal as a preservative. A 38-year-old man treated a mild sore throat himself with a thiomersal spray, and about 30 hours after the second application developed a severe laryngeal obstruction, for which emergency tracheotomy was necessary. A subsequent patch test produced a severe disseminated allergic reaction to thiomersal (SED-11, 484) (50).
Serious allergic reactions were reported in 18 patients after the use of a Japanese encephalitis vaccine containing thiomersal (51). Reactions in 15 patients were thought to be related to the product; 13 had urticaria affecting the whole body, one had erythema multiforme, and one had a rash. Fourteen reactions arose after the second ª 2006 Elsevier B.V. All rights reserved.
immunization. Seven of the 13 urticarial reactions began within 24 hours of vaccination, and the other six within 72 hours. In five patients encephalitis vaccine was the only vaccine given. The thiomersal concentration had been increased from 0.0005% in previous vaccine batches, to 0.0067% in the batch used. However, the concentration of thiomersal was that used in most vaccines. In topical formulations thiomersal can lead to an allergic contact dermatitis. There was a high incidence of thiomersal allergy in patients with pompholyx, that is vesicular eruptions on the palms and soles (48). Thiomersal is more soluble and stable than the older mercurials. It does not influence tear-film wetting of cornea or contact lenses, or the stability of the tear film itself. Thiomersal has been known to cause both a blepharoconjunctivitis and a punctate keratitis in contact lens wearers. Thiomersal keratoconjunctivitis accounted for 32 of 312 consecutive referrals to an outpatient department for problems related to contact lenses (52). The typical appearances included non-specific conjunctival changes, limbal follicles, superficial punctate keratopathy, and superior corneal epithelial opacities. Atypical cases presented with superior limbitis, coarse punctate keratopathy, severe keratopathy with visual loss, pseudodendritic corneal lesions, or acute conjunctival hyperemia without keratopathy. In atypical cases, the diagnosis can be difficult but can be aided by the use of topical challenge with thiomersal. The condition can be incorrectly attributed to allergy. However, a large number of cases of allergic conjunctivitis have been attributed to thiomersal as a constituent of a solution for preserving soft contact lenses (SED-11, 484) (53).
A 26-year-old man with a 2-year history of repeated episodes of dermatitis, swelling of the eyelids, and burning eyes was thought to have delayed contact allergy (54). The original diagnosis was of occupational allergy, but patch tests confirmed that the conjunctivitis was due to thiomersal-containing eye-drops, which had been used to treat the condition.
In an effort to reduce exposure to mercury the FDA have recommended that vaccine manufacturers phase out its use. In response to this, some blood products are also being manufactured free of thiomersal (55). In July 1999 the American Academy of Pediatrics and the US Public Health Service issued a joint statement calling for the removal of thiomersal, a mercury-containing preservative, from vaccines. This action was prompted partly by a risk assessment by the FDA, which consisted of hazard identification, dose–response assessment, exposure assessment, and risk characterization (56). The review showed no evidence of harm caused by the doses of thiomersal in vaccines, except for local hypersensitivity reactions. However, it was noted that some infants may be exposed to cumulative doses of mercury during the first 6 months of life that exceed the Environmental Protection Agency recommendations. In the UK the Committee on Safety of Medicines and the Department of Health reviewed the available data relating to thiomersal in vaccines and possible neurodevelopmental disorders, including autism, an issue that has gained media attention (57). There was no evidence of neurodevelopmental harm, a known effect of acute
Mercury and mercurial salts intoxication with mercury, caused by the amounts of thiomersal that are found in vaccines. The amounts of thiomersal in the UK schedule of childhood vaccination are lower than in the USA. No specific action has been recommended in the vaccination program. European and American regulatory authorities have recommended that vaccine manufacturers should phase out their use of thiomersal whenever possible as a precaution (SEDA-25, 278). Inorganic salts Chronic mercurialism with nervous system involvement, renal insufficiency, and progressive colitis has been described after the long-term use of remedies containing inorganic mercury. Such remedies may also explain the persistence of other unexplained disorders, such as pink disease. Inorganic and organic mercury compounds may cause allergic dermatitis (SEDA-22, 247) (28). Frank poisoning from these sources, although uncommon today, is still possible, and occasional case reports appear (SEDA-13, 195); in one instance, injudicious chronic use of an ammoniated mercury ointment led to a peripheral polyneuropathy, which was only partly reversible (SEDA-22, 247). As with other metals, reactions to mercury can occur after occupational or environmental exposure; in one case, a child already known to be hypersensitive to mercurochrome developed a severe rash after wearing plastic boots which were found to contain mercurous chloride (58). Despite several warnings over many years, the use of mercuric chloride solutions during operations in an attempt to kill cancer cells implanted in healthy tissues persists in some countries. Intraperitoneal administration, when seeding of a visceral cancer is feared, carries the risk of mercury absorption and nephrotoxicity. Death from intoxication after peritoneal lavage with a mercuric chloride solution has been reported (3). Health authorities in Canada have warned consumers ´ a product not to use Diana Cream (Diana de Beaute), that is used for skin lightening, mainly by Afro-Caribbean communities. The Directorate General of Pharmaceutical Affairs & Drug Control has prohibited the registration, import, and sale of the product, which is manufactured in Lebanon and is being illegally imported. It contains ammoniated mercury, bismuth subnitrate, and salicylic acid. The mercury content poses a high risk of mercury poisoning in adults and a serious health hazard to unborn and nursing infants of women who use the product (59). Peripheral polyneuropathy as a result of chronic ammoniated mercury poisoning has been studied and followed over 2 years (60).
A 36-year-old man developed peripheral polyneuropathy after chronic perianal use of an ammoniated mercury ointment. He had very high blood and urine mercury concentrations. Sural nerve biopsy showed mixed axonal degeneration/demyelination. His symptoms improved progressively over 2 years after withdrawal of the ointment, but neurophysiological recovery was incomplete. A 4-month-old boy was hospitalized with a weeping eczema covering more than the half of the body surface and complicated by skin hemorrhage and infection by Klebsiella pneumoniae and Proteus mirabilis. Apart from
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general therapy, a compound zinc oxide ointment containing, among other ingredients, yellow mercuric oxide 2 g per 40 g of base was applied daily. After 12 days, he rapidly developed cardiovascular collapse, acute pulmonary edema, and coma Stage II, with right hemiparesis, generalized hypertonia, and muscular tremor. The mercury concentrations in blood, urine, and CSF were respectively 120 ng/ml (normal <10 ng/ml), creatinine 260 micrograms/g (normal <5 micrograms/g), and 4.8 ng/ml (normal <0.1 ng/ml). Despite therapy with dimercaprol and vigorous supportive measures, the child’s condition deteriorated, he developed Klebsiella aerogenes septicemia, and died 6 weeks later (61).
Organs and Systems Sensory systems Topical treatment with phenylmercuryl acetate can cause band-shaped corneal opacities (62). Long-term use of eye-drops containing phenylmercuric nitrate as a preservative can cause pigmentation of the anterior lens capsule. In 31 patients who used eye-drops containing phenylmercuric nitrate as a preservative for 3–15 years, a brownish pigmentation of the anterior capsule of the pupillary area developed. Light and electron microscopic studies on two lenses showed deposits of dense particulate material resembling melanin pigment on and in the anterior capsule of the lens in the area of the pupil (63). Electron microprobe analysis and neutron activation analysis established the presence of mercury. However, the pigmentation does not seem to be associated with visual impairment. The use of mercurials in the eye can lead to a bluishgray deposit of mercuric oxide on the eyelids, conjunctivae, and Descemet’s layer. Phenylmercuric nitrate used in a 0.004% concentration can cause mercuria lentis. Mercurial compounds have been found in the aqueous humor, having penetrated the eye from hydrophilic-gel contact lenses preserved with thiomersal. Although it remains to be established whether deposition of mercury in the eye is clinically important, the concentrations found are similar to those reported in cases of systemic poisoning by organic mercurials (64). Psychological, psychiatric There is continuing debate that there is an association between autism and thiomersal-containing vaccines. Some authors believe that review of the literature supports the hypothesis that mercury in vaccines may be a factor in the pathogenesis of autism (65). The World Health Organization’s Global Advisory Committee on Vaccine Safety (GACvS) has also kept this issue under review and concluded in November 2002 that there is no evidence of toxicity in infants, children, or adults who have been exposed to thiomersal in vaccines. The CSM is also keeping the issue under close review and studies of the possible toxicology of thiomersal continue to appear (66). The usual dose of ethyl mercury in pediatric vaccines is small (about 12.5–25 micrograms of mercury). However, the metabolism of ethyl mercury in infants who receive
2264 Mercury and mercurial salts vaccines containing thiomersal is unknown. The mean doses of mercury in 40 full-term infants exposed to thiomersal-containing vaccines were 46 (range 38–63) micrograms in 2-month-old children and 111 (range 88–175) micrograms in 6-month-old children. Blood mercury concentrations in the thiomersal-exposed 2-month-old children ranged from less than 3.8 to 21 nmol/l; in 6-month-old children all the concentrations were below 7.5 nmol/l. Only one of 15 blood samples from 21 controls contained measurable concentrations of mercury. Urine concentrations of mercury were low after vaccination, but stool concentrations were high in thiomersal-exposed 2-month-old children (mean 82 ng/g dry weight). The mean half life of ethyl mercury was 7 days. This study was not designed as a formal assessment of the pharmacokinetics of mercury. However, it showed that the administration of vaccines containing thiomersal did not seem to raise blood concentrations of mercury above safe values in infants. Ethyl mercury seems to be eliminated from the blood rapidly via the stools. The authors concluded that the thiomersal in routine vaccines poses very little risk in full-term infants. Urinary tract Membranous glomerulonephritis has been attributed to mercury in a patient with diabetes mellitus.
A 21-year-old man with a 16-year history of diabetes mellitus, who had been using an ointment containing 10% mercuric ammonium chloride for eczema for about 3 weeks, became tired, with fasciculation in the limbs and poor control of his diabetes (67). Nephrotic syndrome and hypertension were diagnosed 1 month later, and at 2 months he was very weak with tremor of the hands, was almost unable to walk, and had lost 20 kg. His behavior suggested an acute psychosis. The urine mercury concentration was 250 micrograms/l. He was treated with sodium 2,3-dimercaptopropane-1-sulfonate (Dimaval) capsules for 12 days (total dose 6.3 g). The highest urine mercury excretion during antidote treatment was 2336 micrograms/day. He had proteinuria of up to 11 g/day and renal biopsy showed diffuse membranous glomerulonephritis without diabetic nephropathy. Similarly, his neuropathy did not have typical features of diabetic neuropathy. He improved over the next year.
Immunologic Merthiolate was tested as a matter of routine in an extended standard series of skin tests in patients with different subtypes of eczema and varicose complex (68). Of 880 patients 53% responded positively to one or more allergens, 3.9% to merthiolate. The latest results of skin tests in adults have confirmed the persistence of contact allergy to merthiolate and justify further follow-up and systematic screening. Attention has been given to mercury as a cause of autoimmune responses, especially in the kidney (69). Exposure to mercury can cause immune responses to various auto-antigens and autoimmune disease of the kidney and other tissues. Although epidemiological studies have shown that occupational exposure to mercury does not usually result in autoimmunity, mercury can cause the formation of antinuclear antibodies, ª 2006 Elsevier B.V. All rights reserved.
scleroderma-like disease, lichen planus, or membranous nephropathy in some individuals. In experimental animals mercury causes autoimmune disease similar to that observed in humans, with emphasis on the importance of immunogenetic and pharmacogenetic factors. Homeopathic medicines can cause mercury allergy (baboon syndrome).
A 5-year-old girl developed an itchy erythematous macular rash, symmetrically distributed in the anogenital area and thighs (70). The lesions developed into a widespread maculopapular vesicular rash in 48 hours, sparing the face, palms, and soles. The eruption cleared after systemic corticosteroids and antihistamines, with scaling and post-inflammatory hypopigmentation. She had had neonatal periumbilical dermatitis associated with the application of merbromin to the cord, and 24 hours before the onset of the rash had taken a single homeopathic tablet (Mercurius Heel), which contained soluble mercury. Allergy tests to a standard series of foods and respiratory allergens were negative and total IgE was normal. Patch-testing to allergens showed positive reactions to thiomersal and metallic mercury.
Previous sensitization and the subsequent development of an allergic contact dermatitis from vaccines that contain thiomersal has received more attention than before (71). Cross-reactivity, exposure factors, and tolerance to vaccines containing thiomersal have been studied in 125 patients sensitized to mercury derivatives in a crosssectional study (71). Childhood vaccinations, merbromin used as an antiseptic, broken thermometers, and the use of drops were the main sources of previous exposure. There was sensitization to thiomersal in 57 patients and 24 had a positive intradermal reaction. Ammoniated mercury elicited positive reactions in 78% of all patients and merbromin in 66%. In most cases (100/125) there was cross-reactivity among different mercury derivatives. Intramuscular thiomersal caused a mild local reaction in only five patients (4% of the total, 9% of thiomersal positive reactions). Most of the patients had positive tests to both organic and inorganic mercury derivatives. Vaccination with thiomersal is relatively safe, even for individuals with delayed type hypersensitivity, since more than 90% of allergic patients tolerated intramuscular challenge tests with thiomersal. However, in such patients it would be advisable to restrict the use of mercurial antiseptics and mercury thermometers.
Drug Administration Drug administration route Mercury toxicity has resulted from the use of an ointment containing mercuric ammonium chloride (67).
References 1. Kern F, Roberts N, Ostlere L, Langtry J, Staughton RC. Ammoniated mercury ointment as a cause of peripheral neuropathy. Dermatologica 1991;183(4):280–2. 2. Harada M. Minamata disease: methylmercury poisoning in Japan caused by environmental pollution. Crit Rev Toxicol 1995;25(1):1–24.
Mercury and mercurial salts 3. Laundy T, Adam AE, Kershaw JB, Rainford DJ. Deaths after peritoneal lavage with mercuric chloride solutions: case report and review of the literature. BMJ (Clin Res Ed) 1984;289(6437):96–8. 4. LeClercq A, Melennec J, Proteau J. Intoxication mercurielle. Concours Med 1973;95:6055. 5. Ciaccio EI. Mercury: therapeutic and toxic aspects. Semin Drug Treat 1971;1(2):177–94. 6. Ward OC, Hingerty D. Pink Disease from cutaneous absorption of mercury. J Ir Med Assoc 1967;60(357):94–5. 7. Boogaard PJ, Houtsma AT, Journee HL, Van Sittert NJ. Effects of exposure to elemental mercury on the nervous system and the kidneys of workers producing natural gas. Arch Environ Health 1996;51(2):108–15. 8. Young E. Ammoniated mercury poisoning. Br J Dermatol 1960;72:449–55. 9. Li AM, Chan MH, Leung TF, Cheung RC, Lam CW, Fok TF. Mercury intoxication presenting with tics. Arch Dis Child 2000;83(2):174–5. 10. Matsumoto J, Natsuaki M. Three cases of mercury allergy. Skin Res 1997;39:48–52. 11. Schwarz S, Husstedt I, Bertram HP, Kuchelmeister K. Amyotrophic lateral sclerosis after accidental injection of mercury. J Neurol Neurosurg Psychiatry 1996; 60(6):698. 12. Hohage H, Otte B, Westermann G, Witta J, Welling U, Zidek W, Heidenreich S. Elemental mercurial poisoning. South Med J 1997;90(10):1033–6. 13. Torres-Alanis O, Garza-Ocanas L, Pineyro-Lopez A. Intravenous self-administration of metallic mercury: report of a case with a 5-year follow-up. J Toxicol Clin Toxicol 1997;35(1):83–7. 14. Lorscheider FL, Vimy MJ. Mercury exposure from ‘‘silver’’ fillings. Lancet 1991;337(8749):1103. 15. Lorscheider FL, Vimy MJ, Summers AO. Mercury exposure from ‘‘silver’’ tooth fillings: emerging evidence questions a traditional dental paradigm. FASEB J 1995; 9(7):504–8. 16. Kupsinel R. Mercury amalgam toxicity: a major common denominator of degenerative disease. J Orthomol Psychiatr 1984;13:240. 17. Dodes JE. The amalgam controversy. An evidence-based analysis. J Am Dent Assoc 2001;132(3):348–56. ¨ 18. Staehle HJ. Gesundheitsstorungen durch Amalgam? [Illnesses caused by amalgam?] Med Klin (Munich) 1998;93(2):99–106. 19. Osborne JW, Albino JE. Psychological and medical effects of mercury intake from dental amalgam. A status report for the American Journal of Dentistry. Am J Dent 1999;12(3):151–6. 20. Adachi A, Horikawa T, Takashima T, Ichihashi M. Mercury-induced nummular dermatitis. J Am Acad Dermatol 2000;43(2 Pt 2):383–5. 21. McGivern B, Pemberton M, Theaker ED, Buchanan JA, Thornhill MH. Delayed and immediate hypersensitivity reactions associated with the use of amalgam. Br Dent J 2000;188(2):73–6. 22. Vena GA, Foti C, Grandolfo M, Angelini G. Mercury exanthem. Contact Dermatitis 1994;31(4):214–16. 23. Unni M. Exfoliative dermatitis due to topical mercury application. Indan J Dermatol Venereol Leprol 1994;60: 56–7. 24. Moszczynski P, Rutowski J, Slowinski S, Bem S, JakusStoga D. Effects of occupational exposure to mercury vapors on T cell and NK-cell populations. Arch Med Res 1996;27(4):503–7. 25. Slee PH, den Ottolander GJ, de Wolff FA. A case of merbromin (Mercurochrome) intoxication possibly resulting in aplastic anemia. Acta Med Scand 1979;205(6):463–6. ª 2006 Elsevier B.V. All rights reserved.
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26. Weber G. Todliche Intoxikation nach Grobscher DreiPhasen-Gerbung. [Fatal intoxication following Grob’s triple-phase tanning.] MMW Munch Med Wochenschr 1977;119(44):1437–8. 27. Camarasa G. Contact dermatitis from mercurochrome. Contact Dermatitis 1976;2(2):120–1. 28. Kanerva L, Tarvainen K, Estlander T, Jolanki R. Occupational allegic contact dermatitis caused by mercury and benzoyl peroxide. Eur J Dermatol 1994;4:359–61. 29. Lohiya G. Asthma and urticaria after hepatitis B vaccination. West J Med 1987;147(3):341. 30. Clements CJ, Ball LK, Ball R, Pratt RD. Thiomersal in vaccines: is removal warranted? Drug Saf 2001;24(8): 567–74. 31. van’t Veen AJ. Vaccines without thiomersal: why so necessary, why so long coming? Drugs 2001;61(5):565–72. 32. Magos L. Review on the toxicity of ethylmercury, including its presence as a preservative in biological and pharmaceutical products. J Appl Toxicol 2001;21(1):1–5. 33. Rohyans J, Walson PD, Wood GA, MacDonald WA. Mercury toxicity following merthiolate ear irrigations. J Pediatr 1984;104(2):311–13. 34. Hodgkinson DJ, Irons GB, Williams TJ. Chemical burns and skin preparation solutions. Surg Gynecol Obstet 1978;147(4):534–6. ¨ 35. Gille J, Goerz G. Thiomersal: Ein haufiges Kontaktallergen. Z Hautkr 1992;67:1049–54. 36. l’Allemand D, Gruters A, Heidemann P, Schurnbrand P. Iodine-induced alterations of thyroid function in newborn infants after prenatal and perinatal exposure to povidone iodine. J Pediatr 1983;102(6):935–8. 37. Epstein S. Sensitivity to merthiolat: a cause of false delayed intradermal reactions: clinical and histological investigations. J Allergy Clin Immunol 1963;34:225. 38. Rudner EJ, Clendenning WE, Epstein E. Epidemiology of contact dermatitis in North America: 1972. Arch Dermatol 1973;108(4):537–40. 39. Massuda T, Honda S, Nakauchi Y, et al. Patch test: the data at the Allergy Clinic of Department of Dermatology of Tokyo University Hospital for the past three years. Jpn J Dermatol Ser B 1970;80:133. 40. Osawa J, Kitamura K, Ikezawa Z, Nakajima H. A probable role for vaccines containing thimerosal in thimerosal hypersensitivity. Contact Dermatitis 1991;24(3):178–82. 41. Hannuksela M, Kousa M, Pirila V. Allergy to ingredients of vehicles. Contact Dermatitis 1976;2(2):105–10. 42. Hjorth N. Sensitivity to organic mercury compounds. Contact Dermatitits Newsletter 1976;1:15. 43. Loechel I, Zschunke E. Zur Aktualit¨at der Quecksilberallergie. [Mercury allergy.] Dermatol Monatsschr 1971;157(8):570–8. 44. Novak M, Kvicalova E, Friedlanderova B. Reactions to merthiolate in infants. Contact Dermatitis 1986;15(5):309–10. 45. Lachapelle JM, Chabeau G, Ducombs G, Lacroix M, ˆ multicentrique relaMartin P, Reuter G, Marot L. Enquete ´ ´ tive a` la frequence des tests epicutan´ es positifs au mercure et au thiomersal. [Multicenter survey related to the frequency of positive patch tests with mercury and thiomersal.] Ann Dermatol Venereol 1988;115(8):793–6. 46. Lisi P, Perno P, Ottaviani M, Morelli P. Minimum eliciting patch test concentration of thimerosal. Contact Dermatitis 1991;24(1):22–6. 47. Kiec-Swierczynska M. Uczulajace dzialanie mertiolatu (preparat odkzzajacy) na podstawie materialu Instytutu Medycyny Pracy w Lodzi. [Allergic reaction to merthiolate (a disinfectant) based on material from the Occupational Medicine Institute in Lodz.] Med Pr 1996;47(2):125–31. 48. Moller H. Merthiolate allergy: a nationwide iatrogenic sensitization. Acta Derm Venereol 1977;57(6):509–17. 49. Aberer W. Vaccination despite thimerosal sensitivity. Contact Dermatitis 1991;24(1):6–10.
2266 Mesna 50. Maibach H. Acute laryngeal obstruction presumed secondary to thiomersal (merthiolate) delayed hypersensitivity. Contact Dermatitis 1975;1(4):221–2. 51. Andersen MM, Ronne T. Side-effects with Japanese encephalitis vaccine. Lancet 1991;337(8748):1044. 52. Wilson-Holt N, Dart JK. Thiomersal keratoconjunctivitis, frequency, clinical spectrum and diagnosis. Eye 1989;3(Pt 5): 581–7. 53. Rietschel RL, Wilson LA. Ocular inflammation in patients using soft contact lenses. Arch Dermatol 1982;118(3):147–9. 54. Iliev D, Wuthrich B. Conjunctivitis to thimerosal mistaken as hay fever. Allergy 1998;53(3):333–4. 55. Sawyer LA. Antibodies for the prevention and treatment of viral diseases. Antiviral Res 2000;47(2):57–77. 56. Ball LK, Ball R, Pratt RD. An assessment of thimerosal use in childhood vaccines. Pediatrics 2001;107(5):1147–54. 57. Current Vaccine and Immunisation Issues. London: Department of Health, 15 Oct 2001. PL/CMO/2001/5. 58. Koch P, Nickolaus G. Allergic contact dermatitis and mercury exanthem due to mercury chloride in plastic boots. Contact Dermatitis 1996;34(6):405–9. 59. Anonymous. Ammoniated mercury in skin lightening cream-warning against use and prohibition. WHO Pharm Newslett 1998;5/6:1. 60. Deleu D, Hanssens Y, al-Salmy HS, Hastie I. Peripheral polyneuropathy due to chronic use of topical ammoniated mercury. J Toxicol Clin Toxicol 1998;36(3):233–7. 61. De Bont B, Lauwerys R, Govaerts H, Moulin D. Yellow mercuric oxide ointment and mercury intoxication. Eur J Pediatr 1986;145(3):217–18. 62. Hugues FC, Le Jeunne C. Systemic and local tolerability of ophthalmic drug formulations. An update. Drug Saf 1993;8(5):365–80. 63. Garron LK, Wood IS, Spencer WH, Hayes TL. A clinical pathologic study of mercurialentis medicamentosus. Trans Am Ophthalmol Soc 1976;74:295–320. 64. Burstein NL. Corneal cytotoxicity of topically applied drugs, vehicles and preservatives. Surv Ophthalmol 1980; 25(1):15–30. 65. Novak M, Klezlova V. [Allergy to merthiolate (Thimerosalum) in a set of standard epicutaneous tests in patients with eczematous diseases and leg ulcer during three periods between 1979 and 1999.] Cesko-Slov Dermatol 2000;75:3–10. 66. Bigazzi PE. Metals and kidney autoimmunity. Environ Health Perspect 1999;107(Suppl 5):753–65. 67. Audicana M, Bernedo N, Gonzalez I, Munoz D, Fernandez E, Gastaminza G. An unusual case of baboon syndrome due to mercury present in a homeopathic medicine. Contact Dermatitis 2001;45(3):185. 68. Audicana MT, Munoz D, del Pozo MD, Fernandez E, Gastaminza G, Fernandez de Corres L. Allergic contact dermatitis from mercury antiseptics and derivatives: study protocol of tolerance to intramuscular injections of thimerosal. Am J Contact Dermat 2002;13(1):3–9. 69. Pelclova D, Lukas E, Urban P, Preiss J, Rysava R, Lebenhart P, Okrouhlik B, Fenclova Z, Lebedova J, Stejskalova A, Ridzon P. Mercury intoxication from skin ointment containing mercuric ammonium chloride. Int Arch Occup Environ Health 2002;75(Suppl):S54–9. 70. Bernard S, Enayati A, Roger H, Binstock T, Redwood L. The role of mercury in the pathogenesis of autism. Mol Psychiatry 2002;7(Suppl 2):S42–3. 71. Pichichero ME, Cernichiari E, Lopreiato J, Treanor J. Mercury concentrations and metabolism in infants receiving vaccines containing thiomersal: a descriptive study. Lancet 2002;360(9347):1737–41.
ª 2006 Elsevier B.V. All rights reserved.
Mescaline General Information Mescaline is one of eight hallucinogenic alkaloids derived from the peyote cactus, slices of which (‘‘peyote buttons’’) have been used in religious rites by North and South American Indian tribes. Mescaline itself is only one of the alkaloids present in peyote, but it produces the same effects as the crude preparation. Chemically, it is related to amfetamine. In doses of some 300–500 mg it depresses nervous system activity and produces visual and occasionally auditory hallucinations, illusions, depersonalization, and depressive symptoms. The total picture can closely resemble that caused by lysergic acid diethylamide. Its physical effects include nausea, tremor, and sweating.
Organs and Systems Psychological, psychiatric The effects of mescaline have been investigated in a psychiatric research study (1). Psychosis induced during the experiment was measured with the Brief Psychiatric Rating Scale and the Paranoid Depression Scale. During use of mescaline neuropsychological measures showed reduced functioning of the right hemisphere. Single photon emission computed tomography (SPECT) studies showed a hyperfrontal pattern, with an emphasis on the right hemisphere. The authors discussed the possible educational value of experimentally induced psychosis in understanding the psychotic state.
Reference 1. Hermle L, Funfgeld M, Oepen G, Botsch H, Borchardt D, Gouzoulis E, Fehrenbach RA, Spitzer M. Mescaline-induced psychopathological, neuropsychological, and neurometabolic effects in normal subjects: experimental psychosis as a tool for psychiatric research. Biol Psychiatry 1992;32(11):976–91.
Mesna General Information Mesna is used to prevent or ameliorate hemorrhagic cystitis produced by the anticancer drugs cyclophosphamide and ifosfamide. It is excreted by the kidney and binds and detoxifies acrolein in the urine; mesna also prevents the breakdown of acrolein precursors. It is also used as a mucolytic. Endotracheal instillation of mesna was compared with instillation of saline in mechanically ventilated patients. Following instillation of mesna, there was a significant increase in maximal airway resistance and impairment of oxygenation with a slight increase in PaCO2 (SEDA-20, 183). A single episode of
Mercury and mercurial salts General Information Mercury is a silver-colored metallic element in fluid form (symbol Hg; atomic no. 80). Its symbol derives from the Greek name for the element hydrargyros. It is found as the sulfide salt in cinnabar, the source of the pigment vermilion. With a few exceptions, the use of metallic mercury in medicine is considered to be outdated; the few exceptions include its use in certain preservatives and in dental amalgam. The radioactive nuclides 197Hg and 203Hg have been used diagnostically, but the amount of mercury involved is very small. Even the mercury thermometer is rapidly being replaced by safer alternative devices. The use of mercury in dermatological therapy should be abandoned because of the risk of mercury intoxication (1). Aryl mercurials that have been used medicinally include phenylmercuric acetate, phenylmercuric nitrate, nitromersol, thiomersal, merbromin (mercurochrome), and mercurobutol. These compounds are variously used as preservatives in drugs, including vaccines, for skin disinfestation, the treatment of infections of the skin and mucosa, and in contraceptive jellies and hemorrhoidal remedies; they have also been used in some cosmetics. The aryl mercurials are better absorbed across the mucous membranes than most inorganic mercury salts. Regrettably, some therapeutic exposure to mercury continues, more particularly generally outside the Western world. Non-prescription laxatives containing mercurial compounds are still sold in some countries. The presence of mercury may not always be divulged on the label. Mercury poisoning can also occur through consumption of fish that have swum in waters that have been contaminated with methyl mercury from industrial waste (Minamata disease) (2). When it was first described, in May 1956, the marine products in Minamata Bay contained high concentrations of mercury (6–36 ppm). Mercury was also found in the hair of patients, their families, and the inhabitants of the Shiranui Sea coastline (maximum 705 ppm). Typical symptoms include sensory disturbances (glove and stocking type), ataxia, dysarthria, constriction of the visual fields, auditory disturbances, and tremor. Mercury poisoning has also been seen in the children of mothers who have eaten contaminated marine life (congenital Minamata disease). Acute and chronic mercury poisoning The characteristic clinical picture of acute mercury poisoning includes sudden profound circulatory collapse with tachycardia, hypotension and peripheral vasoconstriction, ª 2006 Elsevier B.V. All rights reserved.
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vomiting, and bloody diarrhea due to hemorrhagic colitis. Renal insufficiency usually develops within 24 hours and is associated with albuminuria, epithelial cell casts, and red cells in the urine, glycosuria, and aminoaciduria. Oliguria can proceed to complete anuric failure. There is also neutrophilic leukocytosis due to tissue necrosis (SED-11, 483) (3). Symptoms of chronic mercury poisoning have been reviewed (4–6). The symptoms are listed in Table 1. The urinary tract is very sensitive to poisoning by all forms of mercury, a sensitive indicator of early injury being a rise in the urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG) (7). In 70 patients with psoriasis treated with an ointment containing ammoniated mercury, symptoms and signs of mercury poisoning were detected in 33 (8): albuminuria, headache, gingivitis, erythroderma, nausea, dizziness, precordial pain, contact dermatitis, conjunctivitis, epistaxis, keratitis, tremor, neuritis, hematological changes, metallic taste in mouth, and purpura. Acrodynia (‘‘pink disease’’) is thought to be a particular form of mercury hypersensitivity, which can be caused by organic or inorganic mercury; it formerly occurred in young children exposed to teething formulations containing mercury compounds. Typical signs include pink scaling palms and soles, flushed cheeks, pruritus, photophobia, profuse irritability, and insomnia. A modern case of acrodynia involved a patient with congenital agammaglobulinemia who had received merthiolate-containing gammaglobulin injections for 15 years (SEDA-6, 225). Mercury poisoning has been reported in a child who took a Chinese herbal medicine (9).
A 5-year-old Chinese boy developed oral ulceration, mainly affecting the left lateral aspect of his tongue, and 5 weeks later motor and vocal tics. Herpetic ulceration was diagnosed and confirmed by the isolation of
Table 1 The symptoms of chronic mercury poisoning System
Symptom
Cardiovascular Nervous system
Hypertension, hypotension Emotional disturbances, irritability, hypochondria, psychosis, impaired memory, insomnia, tremor, dysarthria, involuntary movements, vertigo, polyneuropathy, paresthesia, headache Corneal opacities and ulcers, conjunctivitis, hypacusis Hyperthyroidism Hypochromic anemia, erythrocytosis, lymphocytosis, neutropenia, aplastic anemia Loose teeth, discoloration of the gums and oral mucosa, mouth ulcers, fetor Anorexia, nausea, vomiting, epigastric pain, diarrhea, constipation Nephrotic syndrome Tylotic eczema, dry skin, skin ulcers, erythroderma Acrodynia, arthritis in the legs Dysmenorrhea
Sensory systems Endocrine Hematologic
Mouth Gastrointestinal Urinary tract Skin Musculoskeletal Reproductive system
2260 Mercury and mercurial salts Herpes simplex virus type 1 from a tongue swab. The lesion improved with oral aciclovir (200 mg five times a day for 5 days), but relapsed a few days later. A local pharmacist prescribed a Chinese medicinal herb mouth spray called ‘‘Watermelon Frost’’, said to be useful in controlling pain and healing difficult mucosal wounds. Over the following weeks his oral symptoms improved but he became irritable and cleared his throat frequently. He developed a transient skin rash on his trunk and motor tics (eye blinking, head turning, and shoulder shrugging). His blood lead concentrations was 0.31 mmol/l (normal below 1.5) and his blood manganese concentration was 246 nmol/l (normal 70–280); his urine arsenic concentration was 10 nmol/mmol creatinine (normal <68). His blood mercury concentration was 83 nmol/l (normal for adults <50). The mercury content of the spray was 878 ppm (2% methyl mercury and 98% inorganic mercury). There was a significant difference in mercury content between different brands and between batches of the same brand of the Chinese medicinal herb. The spray was withdrawn and his tics completely resolved within 4 weeks.
exposed to particularly high levels of mercury. This finding has led to a widespread belief in some countries, supported by certain scientific workers (16), that mercury released from amalgam may be the cause of some hitherto unexplained diseases, and a demand has arisen for the removal of amalgam fillings. A number of case histories have been published of individuals in whom chronic (primarily neurological) disorders appear to have responded to removal of amalgam. Although it is acknowledged that occasional individuals are allergic to metallic mercury, the view that it presents any other risk has generally been contested by the dental profession, citing evidence that the mercury released from amalgam will not accumulate in the body as long as there is adequate renal function. A meta-analysis has shown numerous logical and methodological errors in the antiamalgam literature (17). The author concluded that the evidence supporting the safety of amalgam is compelling. The debate continues (18,19). There have been reports of allergic reactions to dental amalgam.
Metallic mercury Metallic mercury (SEDA-21, 239) is poisonous, and prolonged or acute inhalation can be fatal; organic damage results in a severe chemical pneumonitis. Gingivitis, sometimes proceeding to loss of the teeth, is a wellrecognized consequence of prolonged low-level exposure to the metal. Inhalation of vapor from broken thermometers by persons allergic to mercury or even skin exposure can give rise to allergic contact dermatitis (10). If the liquid metal enters the system, even a small amount can cause complications (SEDA-22, 248), although much of the metal is likely to remain at the site of entry and some will be trapped by the lymphatic system. In one remarkable case, a nurse accidentally pierced her hand with a broken mercury thermometer, and developed amyotrophic lateral sclerosis 3 years later; the causal link was uncertain but there was some reason to believe that the metal had activated a latent predisposition to the disorder (11).
A man who attempted suicide by injecting 40 ml mercury was found to have mercury deposits at the injection site and in the lungs (12). A man who injected mercury intravenously developed malaise and weight loss, and a bilateral cervical adenopathy was found (13).
Dental amalgam Dental amalgam (SEDA-10, 210) (SEDA-15, 233) (14,15) is still used for about 75–80% of single-tooth restorations. The modern amalgam consists of a metallic alloy (silver, tin, and copper, sometimes with small amounts of zinc, indium, and/or palladium) mixed with mercury in a percentage of 40–54% mercury by weight. The resultant plastic mass sets and hardens over a period of 8–24 hours. Contrary to previous belief, measurable amounts of mercury escape from dental amalgam fillings in the form of vapor, ions, and abraded particles, and individuals who are accustomed to chew their food thoroughly are ª 2006 Elsevier B.V. All rights reserved.
A 32-year-old dentist had multiple exudative erythematous pruritic plaques on his limbs and trunk for 3 years (20). Although the eruptions were seen almost throughout the year, his symptoms tended to be worse in the summer. Topical corticosteroids, white petrolatum, and oral antihistamines had given slight relief, and an oral corticosteroid gave him transient relief from the itchy eruptions. Patch tests showed that he reacted to 1% ammoniated mercuric chloride in petrolatum and to 0.05% mercuric chloride in water. It was suggested that his dental amalgam should be removed and that he avoid contact with amalgam during his work. Two weeks later his skin symptoms had dramatically improved, leaving pigmentation. Thereafter he was free of symptoms for several months. However, when he handled amalgam again, similar but less severe eruptions appeared on his legs the next day. Subsequent strict avoidance of amalgam improved his eruptions. A 70-year-old man had multiple coin-sized exudative eczematous plaques on his legs and trunk for several months (20). Various kinds of corticosteroid ointments and white petrolatum as an emollient gave him little relief. Patch tests showed that he reacted to 1% ammoniated mercuric chloride in petrolatum and 0.05% mercuric chloride in water. He had all his dental amalgam removed, and 1 month later his eruption had subsided, leaving pigmentation. A 50-year-old man complained of soreness of the left buccal mucosa and the right side of his tongue, made worse by consuming spicy foods and acidic drinks (21). He had a heavily restored dentition, with asymmetrically distributed white striated and red atrophic lesions on the left buccal mucosa and the right and left borders of the tongue. The lesions were in direct contact with the buccal and palatal surfaces of an old corroding and amalgam restoration and the lingual surface of an amalgam restoration. A provisional diagnosis of a lichenoid reaction to amalgam was made and patch tests showed a strong positive response to mercury and a slightly weaker response to amalgam after 72 hours. One amalgam filling was covered with a bonded porcelain crown
Mercury and mercurial salts
and the other was replaced with glass ionomer cement. Within 2 months he was asymptomatic, and after 12 months the lichenoid lesions had completely resolved. A-57-year-old woman (21) had a recurrent urticarial rash on the skin of her face, scalp, and neck precipitated by restorative dental treatment. The reactions were fully established within 12 hours and would resolve over 2–3 days and be completely gone within 1 week. Patch tests showed a strong reaction to mercury. She was advised that alternative dental materials should be used and that existing amalgam should be removed.
Organic salts Organomercurials have been a common cause of allergic contact dermatitis or rash (22) and even exfoliative dermatitis has been described (23). Some reagents for intracutaneous testing (tuberculin, etc.) may contain thiomersal, which can cause sensitization and thus elicit false-positive delayed-type skin reactions. Mercury compounds inhibit most lymphocyte functions (SEDA-21, 240). An early indicator of an immunological response to mercury exposure, for example in occupational medicine, appears to be a change in the lymphocyte count with a differential increase in T helper cells and a rise in the T helper/T suppressor ratio (24). Merbromin Merbromin (mercurochrome, the disodium salt of 2,7dibromo-4-hydroxymercurifluorescein) is the oldest organic mercurial antiseptic in use, but it is active only as a bacteriostatic agent. In contrast to earlier assumptions, it is absorbed through burned or otherwise absorptive surfaces, and can cause severe and lethal intoxication. High mercury concentrations in blood, urine, and organs have been demonstrated (SED-11, 483). Young children run a particular risk of renal damage from absorption of organic mercury compounds used as antiseptics; in one case, frequent application of merbromin to an omphalocele apparently resulted in anuria, respiratory arrest, and death (SED-8, 520). Neither merbromin nor thiomersal can be considered useful in the management of large omphaloceles.
A patient developed mercury intoxication, including aplastic anemia, after local application of merbromin to an operation wound (SED-11, 483) (25). A 37-year-old patient with burns involving 50% of the body surface was treated by Grob’s three-phase method (2% merbromin, 5% tannic acid, and 10% silver nitrate solutions) (26). By day 6 he had pink-coloured urine and progressively developed restlessness, confusion, and coma, with hypothermia on day 8. He died on day 10 with respiratory arrest. The mercury concentration of the urine was 2170 ng/ml on day 6 and 1250 ng/ml on day 9.
The authors pointed out that merbromin should no longer be used in the treatment of burns. However, good results were reported in a retrospective study on the treatment of second-degree burns in 129 children using the same method (solutions with 7% silver nitrate and 2% merbromin). The authors pointed out that the indication is given only in second-degree burns, with burned surfaces of ª 2006 Elsevier B.V. All rights reserved.
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maximally 10–20% of the body surface, preferably in burn injuries of the trunk and non-mobile areas of the extremities. The most important factor seems to be careful attention to the serum sodium concentration and sufficient substitution with infusion therapy (SED-11, 483). An anaphylactic reaction occurred after local application of merbromin in one patient, and several mercurysensitive patients had severe local reactions in patch tests (SED-11, 483) (27).
Thiomersal Thiomersal (O-ethylmercurithiobenzoic acid), an organic mercurial, was first added to childhood vaccines as a preservative in the 1930s. It contains 50% ethyl mercury by weight. It was the potential for infants to be exposed to cumulative doses of mercury from thiomersal in vaccines that prompted the European Medicines Evaluation Agency and the UK’s Committee on Safety of Medicines (CSM) to recommend that it would be prudent to promote the use of vaccines without thiomersal as a precautionary measure (SEDA-26, 259). Thiomersal is also widely used in cutaneous test solutions and in contact lens cleaners and creams. The danger of toxic effects and the efficacy of thiomersal are similar to those of merbromin. Toxic amounts can be absorbed during omphalocele treatment. The aryl mercurials, such as thiomersal are particularly likely to elicit hypersensitivity reactions (10,28), including attacks of asthma in patients who have received hepatitis B vaccine (29). Ethyl mercury toxicity and sensitization from thiomersal-containing vaccines have been indecisively discussed (30,31). The toxicity of ethyl mercury has also been discussed (32). Fatal mercury (and borate) intoxication has been reported after irrigation of the ear with 0.1% thiomersal and 0.14% sodium borate for purulent otitis media, which was refractory to antibiotic therapy over 4 weeks (SED11, 483) (33). The histories of 25 patients with chemical burns caused by preoperative skin preparation have been reviewed. Thiomersal was the most common agent implicated. The burns did not occur in the main area of preparation, but more peripherally where the solution was in close contact with the skin in the drapes or was more closely applied to the skin by pressure, either because of the patient’s own weight or to tourniquet dressings. No burning occurred under a sterile wound drape (although solutions stagnate at this site and do not evaporate), perhaps because there was no pressure. There are particular risks in patients placed in the lithotomy position to undergo gynecological operations (the burns being on the buttocks), and in those undergoing orthopedic operations (the burns then being on the extremities and under a tourniquet) (SED-11, 483) (34). Thiomersal is one of the most frequent sensitizers in the world (3,35). It is used as a preservative in vaccines, test solutions, and topically administered applications, for example creams and solutions used on eczematous skin, ear-drops, eye-drops, and cleanser solutions for ocular contact lenses. The concentration of thiomersal varies between 0.0005 and 0.01% in these formulations. Sensitization can be provoked by immunization with thiomersal-containing vaccines. Even in sensitized
2262 Mercury and mercurial salts patients, thiomersal-induced adverse effects due to immunization has not been shown to be a severe risk, and a positive patch test to thiomersal does not represent a contraindication to immunization with thiomersalcontaining vaccines. Many of the reactions seen in patch tests with 0.1% thiomersal are probably caused by the irritant nature of thiomersal. It has been pointed out that only half of a series of subjects tested with a solution of 0.1% thiomersal had a positive reaction in patch tests with concentrations of 0.05 and 0.01% (36). Thiomersal included in patch-test series has given varying frequencies of positive reactions. Cross-reactions occur to a few organic mercurials, but not to inorganic or metallic mercury. The allergic determinant seems to be the ethyl mercury radical in thiomersal. Frequencies of positive reactions have been reported in the following countries:
USA: 13.4% in 1967 (37) and 8% in 1972 (38) Japan: 5.6 (39) and 16.3% (40) Finland: 2.0% (41) Denmark: 1.3% (42) GDR: 6.9% (43) Czechoslovakia: 5.3% in infant inpatients (44) France and Belgium: 2.3% in a multicenter study in 200 adult patients submitted to routine patch-testing (45) Italy: 5.3% (46) Poland: 5.7% (13.8% of all medicinal personnel, tested in this study) (47).
There was a very high peak frequency of positive patch tests in the 20–30 years age group in Sweden (48): 16% of male recruits and 10% of other healthy subjects in nursing schools and among medical students. A common reason for sensitization to thiomersal in the younger generation in Sweden arises from intracutaneous testing with tuberculin containing thiomersal as a preservative. It was shown experimentally that tuberculin could act as adjuvant during sensitization to thiomersal. The iatrogenic occurrence of thiomersal allergy in the Swedish population does not result in eczematous reactions, but merely in false-positive skin tests. Thiomersal takes second place, after nickel, as a contact allergen in Austria. As in Sweden this high incidence is probably due also to frequent immunization with vaccines containing thiomersal (49).
A generalized allergic reaction occurred in a 50-yearold nurse with a documented allergy to thiomersal, who received 10 ml of human euglobulin with thiomersal as a preservative. A 38-year-old man treated a mild sore throat himself with a thiomersal spray, and about 30 hours after the second application developed a severe laryngeal obstruction, for which emergency tracheotomy was necessary. A subsequent patch test produced a severe disseminated allergic reaction to thiomersal (SED-11, 484) (50).
Serious allergic reactions were reported in 18 patients after the use of a Japanese encephalitis vaccine containing thiomersal (51). Reactions in 15 patients were thought to be related to the product; 13 had urticaria affecting the whole body, one had erythema multiforme, and one had a rash. Fourteen reactions arose after the second ª 2006 Elsevier B.V. All rights reserved.
immunization. Seven of the 13 urticarial reactions began within 24 hours of vaccination, and the other six within 72 hours. In five patients encephalitis vaccine was the only vaccine given. The thiomersal concentration had been increased from 0.0005% in previous vaccine batches, to 0.0067% in the batch used. However, the concentration of thiomersal was that used in most vaccines. In topical formulations thiomersal can lead to an allergic contact dermatitis. There was a high incidence of thiomersal allergy in patients with pompholyx, that is vesicular eruptions on the palms and soles (48). Thiomersal is more soluble and stable than the older mercurials. It does not influence tear-film wetting of cornea or contact lenses, or the stability of the tear film itself. Thiomersal has been known to cause both a blepharoconjunctivitis and a punctate keratitis in contact lens wearers. Thiomersal keratoconjunctivitis accounted for 32 of 312 consecutive referrals to an outpatient department for problems related to contact lenses (52). The typical appearances included non-specific conjunctival changes, limbal follicles, superficial punctate keratopathy, and superior corneal epithelial opacities. Atypical cases presented with superior limbitis, coarse punctate keratopathy, severe keratopathy with visual loss, pseudodendritic corneal lesions, or acute conjunctival hyperemia without keratopathy. In atypical cases, the diagnosis can be difficult but can be aided by the use of topical challenge with thiomersal. The condition can be incorrectly attributed to allergy. However, a large number of cases of allergic conjunctivitis have been attributed to thiomersal as a constituent of a solution for preserving soft contact lenses (SED-11, 484) (53).
A 26-year-old man with a 2-year history of repeated episodes of dermatitis, swelling of the eyelids, and burning eyes was thought to have delayed contact allergy (54). The original diagnosis was of occupational allergy, but patch tests confirmed that the conjunctivitis was due to thiomersal-containing eye-drops, which had been used to treat the condition.
In an effort to reduce exposure to mercury the FDA have recommended that vaccine manufacturers phase out its use. In response to this, some blood products are also being manufactured free of thiomersal (55). In July 1999 the American Academy of Pediatrics and the US Public Health Service issued a joint statement calling for the removal of thiomersal, a mercury-containing preservative, from vaccines. This action was prompted partly by a risk assessment by the FDA, which consisted of hazard identification, dose–response assessment, exposure assessment, and risk characterization (56). The review showed no evidence of harm caused by the doses of thiomersal in vaccines, except for local hypersensitivity reactions. However, it was noted that some infants may be exposed to cumulative doses of mercury during the first 6 months of life that exceed the Environmental Protection Agency recommendations. In the UK the Committee on Safety of Medicines and the Department of Health reviewed the available data relating to thiomersal in vaccines and possible neurodevelopmental disorders, including autism, an issue that has gained media attention (57). There was no evidence of neurodevelopmental harm, a known effect of acute
Mercury and mercurial salts intoxication with mercury, caused by the amounts of thiomersal that are found in vaccines. The amounts of thiomersal in the UK schedule of childhood vaccination are lower than in the USA. No specific action has been recommended in the vaccination program. European and American regulatory authorities have recommended that vaccine manufacturers should phase out their use of thiomersal whenever possible as a precaution (SEDA-25, 278). Inorganic salts Chronic mercurialism with nervous system involvement, renal insufficiency, and progressive colitis has been described after the long-term use of remedies containing inorganic mercury. Such remedies may also explain the persistence of other unexplained disorders, such as pink disease. Inorganic and organic mercury compounds may cause allergic dermatitis (SEDA-22, 247) (28). Frank poisoning from these sources, although uncommon today, is still possible, and occasional case reports appear (SEDA-13, 195); in one instance, injudicious chronic use of an ammoniated mercury ointment led to a peripheral polyneuropathy, which was only partly reversible (SEDA-22, 247). As with other metals, reactions to mercury can occur after occupational or environmental exposure; in one case, a child already known to be hypersensitive to mercurochrome developed a severe rash after wearing plastic boots which were found to contain mercurous chloride (58). Despite several warnings over many years, the use of mercuric chloride solutions during operations in an attempt to kill cancer cells implanted in healthy tissues persists in some countries. Intraperitoneal administration, when seeding of a visceral cancer is feared, carries the risk of mercury absorption and nephrotoxicity. Death from intoxication after peritoneal lavage with a mercuric chloride solution has been reported (3). Health authorities in Canada have warned consumers ´ a product not to use Diana Cream (Diana de Beaute), that is used for skin lightening, mainly by Afro-Caribbean communities. The Directorate General of Pharmaceutical Affairs & Drug Control has prohibited the registration, import, and sale of the product, which is manufactured in Lebanon and is being illegally imported. It contains ammoniated mercury, bismuth subnitrate, and salicylic acid. The mercury content poses a high risk of mercury poisoning in adults and a serious health hazard to unborn and nursing infants of women who use the product (59). Peripheral polyneuropathy as a result of chronic ammoniated mercury poisoning has been studied and followed over 2 years (60).
A 36-year-old man developed peripheral polyneuropathy after chronic perianal use of an ammoniated mercury ointment. He had very high blood and urine mercury concentrations. Sural nerve biopsy showed mixed axonal degeneration/demyelination. His symptoms improved progressively over 2 years after withdrawal of the ointment, but neurophysiological recovery was incomplete. A 4-month-old boy was hospitalized with a weeping eczema covering more than the half of the body surface and complicated by skin hemorrhage and infection by Klebsiella pneumoniae and Proteus mirabilis. Apart from
ª 2006 Elsevier B.V. All rights reserved.
2263
general therapy, a compound zinc oxide ointment containing, among other ingredients, yellow mercuric oxide 2 g per 40 g of base was applied daily. After 12 days, he rapidly developed cardiovascular collapse, acute pulmonary edema, and coma Stage II, with right hemiparesis, generalized hypertonia, and muscular tremor. The mercury concentrations in blood, urine, and CSF were respectively 120 ng/ml (normal <10 ng/ml), creatinine 260 micrograms/g (normal <5 micrograms/g), and 4.8 ng/ml (normal <0.1 ng/ml). Despite therapy with dimercaprol and vigorous supportive measures, the child’s condition deteriorated, he developed Klebsiella aerogenes septicemia, and died 6 weeks later (61).
Organs and Systems Sensory systems Topical treatment with phenylmercuryl acetate can cause band-shaped corneal opacities (62). Long-term use of eye-drops containing phenylmercuric nitrate as a preservative can cause pigmentation of the anterior lens capsule. In 31 patients who used eye-drops containing phenylmercuric nitrate as a preservative for 3–15 years, a brownish pigmentation of the anterior capsule of the pupillary area developed. Light and electron microscopic studies on two lenses showed deposits of dense particulate material resembling melanin pigment on and in the anterior capsule of the lens in the area of the pupil (63). Electron microprobe analysis and neutron activation analysis established the presence of mercury. However, the pigmentation does not seem to be associated with visual impairment. The use of mercurials in the eye can lead to a bluishgray deposit of mercuric oxide on the eyelids, conjunctivae, and Descemet’s layer. Phenylmercuric nitrate used in a 0.004% concentration can cause mercuria lentis. Mercurial compounds have been found in the aqueous humor, having penetrated the eye from hydrophilic-gel contact lenses preserved with thiomersal. Although it remains to be established whether deposition of mercury in the eye is clinically important, the concentrations found are similar to those reported in cases of systemic poisoning by organic mercurials (64). Psychological, psychiatric There is continuing debate that there is an association between autism and thiomersal-containing vaccines. Some authors believe that review of the literature supports the hypothesis that mercury in vaccines may be a factor in the pathogenesis of autism (65). The World Health Organization’s Global Advisory Committee on Vaccine Safety (GACvS) has also kept this issue under review and concluded in November 2002 that there is no evidence of toxicity in infants, children, or adults who have been exposed to thiomersal in vaccines. The CSM is also keeping the issue under close review and studies of the possible toxicology of thiomersal continue to appear (66). The usual dose of ethyl mercury in pediatric vaccines is small (about 12.5–25 micrograms of mercury). However, the metabolism of ethyl mercury in infants who receive
2264 Mercury and mercurial salts vaccines containing thiomersal is unknown. The mean doses of mercury in 40 full-term infants exposed to thiomersal-containing vaccines were 46 (range 38–63) micrograms in 2-month-old children and 111 (range 88–175) micrograms in 6-month-old children. Blood mercury concentrations in the thiomersal-exposed 2-month-old children ranged from less than 3.8 to 21 nmol/l; in 6-month-old children all the concentrations were below 7.5 nmol/l. Only one of 15 blood samples from 21 controls contained measurable concentrations of mercury. Urine concentrations of mercury were low after vaccination, but stool concentrations were high in thiomersal-exposed 2-month-old children (mean 82 ng/g dry weight). The mean half life of ethyl mercury was 7 days. This study was not designed as a formal assessment of the pharmacokinetics of mercury. However, it showed that the administration of vaccines containing thiomersal did not seem to raise blood concentrations of mercury above safe values in infants. Ethyl mercury seems to be eliminated from the blood rapidly via the stools. The authors concluded that the thiomersal in routine vaccines poses very little risk in full-term infants. Urinary tract Membranous glomerulonephritis has been attributed to mercury in a patient with diabetes mellitus.
A 21-year-old man with a 16-year history of diabetes mellitus, who had been using an ointment containing 10% mercuric ammonium chloride for eczema for about 3 weeks, became tired, with fasciculation in the limbs and poor control of his diabetes (67). Nephrotic syndrome and hypertension were diagnosed 1 month later, and at 2 months he was very weak with tremor of the hands, was almost unable to walk, and had lost 20 kg. His behavior suggested an acute psychosis. The urine mercury concentration was 250 micrograms/l. He was treated with sodium 2,3-dimercaptopropane-1-sulfonate (Dimaval) capsules for 12 days (total dose 6.3 g). The highest urine mercury excretion during antidote treatment was 2336 micrograms/day. He had proteinuria of up to 11 g/day and renal biopsy showed diffuse membranous glomerulonephritis without diabetic nephropathy. Similarly, his neuropathy did not have typical features of diabetic neuropathy. He improved over the next year.
Immunologic Merthiolate was tested as a matter of routine in an extended standard series of skin tests in patients with different subtypes of eczema and varicose complex (68). Of 880 patients 53% responded positively to one or more allergens, 3.9% to merthiolate. The latest results of skin tests in adults have confirmed the persistence of contact allergy to merthiolate and justify further follow-up and systematic screening. Attention has been given to mercury as a cause of autoimmune responses, especially in the kidney (69). Exposure to mercury can cause immune responses to various auto-antigens and autoimmune disease of the kidney and other tissues. Although epidemiological studies have shown that occupational exposure to mercury does not usually result in autoimmunity, mercury can cause the formation of antinuclear antibodies, ª 2006 Elsevier B.V. All rights reserved.
scleroderma-like disease, lichen planus, or membranous nephropathy in some individuals. In experimental animals mercury causes autoimmune disease similar to that observed in humans, with emphasis on the importance of immunogenetic and pharmacogenetic factors. Homeopathic medicines can cause mercury allergy (baboon syndrome).
A 5-year-old girl developed an itchy erythematous macular rash, symmetrically distributed in the anogenital area and thighs (70). The lesions developed into a widespread maculopapular vesicular rash in 48 hours, sparing the face, palms, and soles. The eruption cleared after systemic corticosteroids and antihistamines, with scaling and post-inflammatory hypopigmentation. She had had neonatal periumbilical dermatitis associated with the application of merbromin to the cord, and 24 hours before the onset of the rash had taken a single homeopathic tablet (Mercurius Heel), which contained soluble mercury. Allergy tests to a standard series of foods and respiratory allergens were negative and total IgE was normal. Patch-testing to allergens showed positive reactions to thiomersal and metallic mercury.
Previous sensitization and the subsequent development of an allergic contact dermatitis from vaccines that contain thiomersal has received more attention than before (71). Cross-reactivity, exposure factors, and tolerance to vaccines containing thiomersal have been studied in 125 patients sensitized to mercury derivatives in a crosssectional study (71). Childhood vaccinations, merbromin used as an antiseptic, broken thermometers, and the use of drops were the main sources of previous exposure. There was sensitization to thiomersal in 57 patients and 24 had a positive intradermal reaction. Ammoniated mercury elicited positive reactions in 78% of all patients and merbromin in 66%. In most cases (100/125) there was cross-reactivity among different mercury derivatives. Intramuscular thiomersal caused a mild local reaction in only five patients (4% of the total, 9% of thiomersal positive reactions). Most of the patients had positive tests to both organic and inorganic mercury derivatives. Vaccination with thiomersal is relatively safe, even for individuals with delayed type hypersensitivity, since more than 90% of allergic patients tolerated intramuscular challenge tests with thiomersal. However, in such patients it would be advisable to restrict the use of mercurial antiseptics and mercury thermometers.
Drug Administration Drug administration route Mercury toxicity has resulted from the use of an ointment containing mercuric ammonium chloride (67).
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26. Weber G. Todliche Intoxikation nach Grobscher DreiPhasen-Gerbung. [Fatal intoxication following Grob’s triple-phase tanning.] MMW Munch Med Wochenschr 1977;119(44):1437–8. 27. Camarasa G. Contact dermatitis from mercurochrome. Contact Dermatitis 1976;2(2):120–1. 28. Kanerva L, Tarvainen K, Estlander T, Jolanki R. Occupational allegic contact dermatitis caused by mercury and benzoyl peroxide. Eur J Dermatol 1994;4:359–61. 29. Lohiya G. Asthma and urticaria after hepatitis B vaccination. West J Med 1987;147(3):341. 30. Clements CJ, Ball LK, Ball R, Pratt RD. Thiomersal in vaccines: is removal warranted? Drug Saf 2001;24(8): 567–74. 31. van’t Veen AJ. Vaccines without thiomersal: why so necessary, why so long coming? Drugs 2001;61(5):565–72. 32. Magos L. Review on the toxicity of ethylmercury, including its presence as a preservative in biological and pharmaceutical products. J Appl Toxicol 2001;21(1):1–5. 33. Rohyans J, Walson PD, Wood GA, MacDonald WA. Mercury toxicity following merthiolate ear irrigations. J Pediatr 1984;104(2):311–13. 34. Hodgkinson DJ, Irons GB, Williams TJ. Chemical burns and skin preparation solutions. Surg Gynecol Obstet 1978;147(4):534–6. ¨ 35. Gille J, Goerz G. Thiomersal: Ein haufiges Kontaktallergen. Z Hautkr 1992;67:1049–54. 36. l’Allemand D, Gruters A, Heidemann P, Schurnbrand P. Iodine-induced alterations of thyroid function in newborn infants after prenatal and perinatal exposure to povidone iodine. J Pediatr 1983;102(6):935–8. 37. Epstein S. Sensitivity to merthiolat: a cause of false delayed intradermal reactions: clinical and histological investigations. J Allergy Clin Immunol 1963;34:225. 38. Rudner EJ, Clendenning WE, Epstein E. Epidemiology of contact dermatitis in North America: 1972. Arch Dermatol 1973;108(4):537–40. 39. Massuda T, Honda S, Nakauchi Y, et al. Patch test: the data at the Allergy Clinic of Department of Dermatology of Tokyo University Hospital for the past three years. Jpn J Dermatol Ser B 1970;80:133. 40. Osawa J, Kitamura K, Ikezawa Z, Nakajima H. A probable role for vaccines containing thimerosal in thimerosal hypersensitivity. Contact Dermatitis 1991;24(3):178–82. 41. Hannuksela M, Kousa M, Pirila V. Allergy to ingredients of vehicles. Contact Dermatitis 1976;2(2):105–10. 42. Hjorth N. Sensitivity to organic mercury compounds. Contact Dermatitits Newsletter 1976;1:15. 43. Loechel I, Zschunke E. Zur Aktualit¨at der Quecksilberallergie. [Mercury allergy.] Dermatol Monatsschr 1971;157(8):570–8. 44. Novak M, Kvicalova E, Friedlanderova B. Reactions to merthiolate in infants. Contact Dermatitis 1986;15(5):309–10. 45. Lachapelle JM, Chabeau G, Ducombs G, Lacroix M, ˆ multicentrique relaMartin P, Reuter G, Marot L. Enquete ´ ´ tive a` la frequence des tests epicutan´ es positifs au mercure et au thiomersal. [Multicenter survey related to the frequency of positive patch tests with mercury and thiomersal.] Ann Dermatol Venereol 1988;115(8):793–6. 46. Lisi P, Perno P, Ottaviani M, Morelli P. Minimum eliciting patch test concentration of thimerosal. Contact Dermatitis 1991;24(1):22–6. 47. Kiec-Swierczynska M. Uczulajace dzialanie mertiolatu (preparat odkzzajacy) na podstawie materialu Instytutu Medycyny Pracy w Lodzi. [Allergic reaction to merthiolate (a disinfectant) based on material from the Occupational Medicine Institute in Lodz.] Med Pr 1996;47(2):125–31. 48. Moller H. Merthiolate allergy: a nationwide iatrogenic sensitization. Acta Derm Venereol 1977;57(6):509–17. 49. Aberer W. Vaccination despite thimerosal sensitivity. Contact Dermatitis 1991;24(1):6–10.
2266 Mesna 50. Maibach H. Acute laryngeal obstruction presumed secondary to thiomersal (merthiolate) delayed hypersensitivity. Contact Dermatitis 1975;1(4):221–2. 51. Andersen MM, Ronne T. Side-effects with Japanese encephalitis vaccine. Lancet 1991;337(8748):1044. 52. Wilson-Holt N, Dart JK. Thiomersal keratoconjunctivitis, frequency, clinical spectrum and diagnosis. Eye 1989;3(Pt 5): 581–7. 53. Rietschel RL, Wilson LA. Ocular inflammation in patients using soft contact lenses. Arch Dermatol 1982;118(3):147–9. 54. Iliev D, Wuthrich B. Conjunctivitis to thimerosal mistaken as hay fever. Allergy 1998;53(3):333–4. 55. Sawyer LA. Antibodies for the prevention and treatment of viral diseases. Antiviral Res 2000;47(2):57–77. 56. Ball LK, Ball R, Pratt RD. An assessment of thimerosal use in childhood vaccines. Pediatrics 2001;107(5):1147–54. 57. Current Vaccine and Immunisation Issues. London: Department of Health, 15 Oct 2001. PL/CMO/2001/5. 58. Koch P, Nickolaus G. Allergic contact dermatitis and mercury exanthem due to mercury chloride in plastic boots. Contact Dermatitis 1996;34(6):405–9. 59. Anonymous. Ammoniated mercury in skin lightening cream-warning against use and prohibition. WHO Pharm Newslett 1998;5/6:1. 60. Deleu D, Hanssens Y, al-Salmy HS, Hastie I. Peripheral polyneuropathy due to chronic use of topical ammoniated mercury. J Toxicol Clin Toxicol 1998;36(3):233–7. 61. De Bont B, Lauwerys R, Govaerts H, Moulin D. Yellow mercuric oxide ointment and mercury intoxication. Eur J Pediatr 1986;145(3):217–18. 62. Hugues FC, Le Jeunne C. Systemic and local tolerability of ophthalmic drug formulations. An update. Drug Saf 1993;8(5):365–80. 63. Garron LK, Wood IS, Spencer WH, Hayes TL. A clinical pathologic study of mercurialentis medicamentosus. Trans Am Ophthalmol Soc 1976;74:295–320. 64. Burstein NL. Corneal cytotoxicity of topically applied drugs, vehicles and preservatives. Surv Ophthalmol 1980; 25(1):15–30. 65. Novak M, Klezlova V. [Allergy to merthiolate (Thimerosalum) in a set of standard epicutaneous tests in patients with eczematous diseases and leg ulcer during three periods between 1979 and 1999.] Cesko-Slov Dermatol 2000;75:3–10. 66. Bigazzi PE. Metals and kidney autoimmunity. Environ Health Perspect 1999;107(Suppl 5):753–65. 67. Audicana M, Bernedo N, Gonzalez I, Munoz D, Fernandez E, Gastaminza G. An unusual case of baboon syndrome due to mercury present in a homeopathic medicine. Contact Dermatitis 2001;45(3):185. 68. Audicana MT, Munoz D, del Pozo MD, Fernandez E, Gastaminza G, Fernandez de Corres L. Allergic contact dermatitis from mercury antiseptics and derivatives: study protocol of tolerance to intramuscular injections of thimerosal. Am J Contact Dermat 2002;13(1):3–9. 69. Pelclova D, Lukas E, Urban P, Preiss J, Rysava R, Lebenhart P, Okrouhlik B, Fenclova Z, Lebedova J, Stejskalova A, Ridzon P. Mercury intoxication from skin ointment containing mercuric ammonium chloride. Int Arch Occup Environ Health 2002;75(Suppl):S54–9. 70. Bernard S, Enayati A, Roger H, Binstock T, Redwood L. The role of mercury in the pathogenesis of autism. Mol Psychiatry 2002;7(Suppl 2):S42–3. 71. Pichichero ME, Cernichiari E, Lopreiato J, Treanor J. Mercury concentrations and metabolism in infants receiving vaccines containing thiomersal: a descriptive study. Lancet 2002;360(9347):1737–41.
ª 2006 Elsevier B.V. All rights reserved.
Mescaline General Information Mescaline is one of eight hallucinogenic alkaloids derived from the peyote cactus, slices of which (‘‘peyote buttons’’) have been used in religious rites by North and South American Indian tribes. Mescaline itself is only one of the alkaloids present in peyote, but it produces the same effects as the crude preparation. Chemically, it is related to amfetamine. In doses of some 300–500 mg it depresses nervous system activity and produces visual and occasionally auditory hallucinations, illusions, depersonalization, and depressive symptoms. The total picture can closely resemble that caused by lysergic acid diethylamide. Its physical effects include nausea, tremor, and sweating.
Organs and Systems Psychological, psychiatric The effects of mescaline have been investigated in a psychiatric research study (1). Psychosis induced during the experiment was measured with the Brief Psychiatric Rating Scale and the Paranoid Depression Scale. During use of mescaline neuropsychological measures showed reduced functioning of the right hemisphere. Single photon emission computed tomography (SPECT) studies showed a hyperfrontal pattern, with an emphasis on the right hemisphere. The authors discussed the possible educational value of experimentally induced psychosis in understanding the psychotic state.
Reference 1. Hermle L, Funfgeld M, Oepen G, Botsch H, Borchardt D, Gouzoulis E, Fehrenbach RA, Spitzer M. Mescaline-induced psychopathological, neuropsychological, and neurometabolic effects in normal subjects: experimental psychosis as a tool for psychiatric research. Biol Psychiatry 1992;32(11):976–91.
Mesna General Information Mesna is used to prevent or ameliorate hemorrhagic cystitis produced by the anticancer drugs cyclophosphamide and ifosfamide. It is excreted by the kidney and binds and detoxifies acrolein in the urine; mesna also prevents the breakdown of acrolein precursors. It is also used as a mucolytic. Endotracheal instillation of mesna was compared with instillation of saline in mechanically ventilated patients. Following instillation of mesna, there was a significant increase in maximal airway resistance and impairment of oxygenation with a slight increase in PaCO2 (SEDA-20, 183). A single episode of