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Review |
Address correspondence to Kern Nuttall, M.D., Ph.D., 2112 Birch Circle, Bellingham, WA 98229, USA; tel 360 647-5212; e-mail: kern_nuttall{at}yahoo.com.
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Abstract |
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 Top Abstract IntroductionNomenclature and Basic...Routes of ExposureDosePatient FactorsMetabolismPublished ReportsEvaluating Mercury ResultsReferences |
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(received 8 March 2004; accepted 19 May 2004)
Keywords: Heavy metals, mercury poisoning, mercury metabolism, porphyrins, biological markers
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Introduction |
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TopAbstractIntroductionNomenclature and Basic...Routes of ExposureDosePatient FactorsMetabolismPublished ReportsEvaluating Mercury ResultsReferences |
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Although the treatment of mercury poisoning is not reviewed here, several points are worth summarizing: (a) the most important aspects of treatment are supportive care and the prevention of further exposure, (b) the object of treatment is improvement in the patient and not in the laboratory values, and (c) chelation treatment is most appropriate for patients who show significant signs and symptoms of toxicity. While chelation increases mercury excretion, the benefits of doing so have not been established in asymptomatic individuals. Common adverse effects of chelating agents include abdominal cramps, drowsiness, dizziness, rash, pruritus, and flu-like symptoms [3].
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Nomenclature and Basic Biochemistry |
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TopAbstractIntroductionNomenclature and Basic...Routes of ExposureDosePatient FactorsMetabolismPublished ReportsEvaluating Mercury ResultsReferences |
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Mercury(0) is also known as elemental or metallic mercury, and is a dense, silver-grey liquid at room temperature. When mercury(0) is oxidized to mercury(I) and (II), it forms compounds with various electron donors. Mercury bound to a carbon atom is ‘organic mercury,’ examples of which include methylmercury and ethylmercury. Organic mercury is always mercury(II) [4]. When not bound to carbon, mercury is ‘inorganic.’
Although other reactions occur, the principal reaction of mercury in biological systems is with sulfhydryl (-SH) groups [5]. The predominant biological sulfhydryl compound is the amino acid cysteine. Toxicity is caused primarily by mercury binding and inactivation of cysteine residues in enzymes and structural proteins. Metallothioneins, a family of cysteine-rich proteins, and glutathione play protective roles. Chelation treatment to increase mercury excretion employs sulfhydryl compounds such as 2,3-dimercaptosuccinic acid (DMSA) and sodium 2,3-dimercapto-1-propane sulfonate (DMPS) [3].
Methylmercury nomenclature. Some terms in the mercury literature are used loosely and it is helpful to define the context carefully. The label ‘methyl-mercury’ on a reagent bottle refers to dimethyl-mercury (H3C-Hg-CH3) [6], a dense, concentrated liquid that is insoluble in water and highly dangerous to handle [7]. In contrast, methylmercury in fish and other foodstuffs refers to the methylmercury ion (H3C-Hg+) and to the adducts it forms with sulfhydryl ligands (H3C-Hg-S-R) [8]. The adduct methylmercury cysteine is water soluble and considerably less toxic than the closely related compound, methylmercury chloride [9]. Since the mercury-chloride bond (H3C-Hg-Cl) is largely covalent and remains intact even in dilute aqueous solution, methylmercury chloride is not equivalent to methylmercury ion.
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Routes of Exposure |
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TopAbstractIntroductionNomenclature and Basic...Routes of ExposureDosePatient FactorsMetabolismPublished ReportsEvaluating Mercury ResultsReferences |
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Inhalation. Due to its volatility, mercury(0) is responsible for most cases of inhalation exposure. Heating increases its volatility and the intensity of exposure. Heating cinnabar, the mineral form of mercury(II) sulfide, can release mercury(0) and has been associated with fatal inhalation [10]. Many organic compounds such as dimethylmercury are also volatile [4].
Ingestion. Mercury(II) chloride (HgCl2) is soluble in water and organic solvents, and is markedly toxic when ingested in sufficiently high dose [11]. In contrast, mercury(0) and mercury(I) chloride (Hg2Cl2) are insoluble in both water and lipid environments [4], and therefore show low toxicity by oral ingestion. Mercury(I) chloride is an historically important laxative and vermifuge commonly known as ‘calomel’ and ‘mild mercury chloride’ [6]. It is not dependable as a non-toxic laxative, however, because it easily degrades to give mercury(II) chloride and mercury(0).
Cutaneous. Cutaneous absorption is probable for mercury compounds that are lipid soluble, particularly with prolonged contact and high concentrations. Mercury(II) chloride is soluble in organic solvents (1 g in 200 ml benzene [6]), whereas mercury(0) and mercury(I) chloride are much less soluble. A limited amount of mercury(0) can be absorbed directly through the intact skin, but its release into the circulation is slow and of little practical significance [12].
Reagent dimethylmercury is rapidly absorbed through the skin, even when latex gloves are worn [7]. Cutaneous absorption has been claimed for ‘beauty creams’ containing high concentrations of mercury(I) chloride [13]. While significant exposure clearly occurs with these products, it is more likely to proceed through decomposition to mercury(0) and mercury(II). Cutaneous absorption is more probable for ‘skin-whitening creams’ containing ‘ammoniated mercury’[14], known as mercury(II) ammonium chloride (Cl-Hg-NH2) [6]. Some inadvertent oral ingestion may also be likely.
Injection. Injection of liquid mercury(0) results in droplets that become trapped in sites such as the pulmonary capillary bed [15]. Water insolubility and low surface area render these particles relatively inert compared to dissolved mercury(0) vapor. Liquid mercury(0) deposited subcutaneously is stable for years. In contrast, water soluble mercury compounds injected subcutaneously can cause local tissue destruction within days.
Red pigments in tattoos may include the red isomer of mercury(II) sulfide (vermillion, cinnabar). This compound is insoluble in water (~1 x 10–6 g/ 100 g [4]) and remains largely inert when injected subcutaneously. A limited number of people with such tattoos experience inflammation restricted to the site of pigment deposition, usually within 6 months of tattooing [16]. This is an immune-based allergic response and mercury(II) sulfide is unlikely to contribute to blood or urine mercury levels.
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Dose |
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Acute effects. An example of acute mercury toxicity is seen with the flu-like syndrome that can develop after high-dose inhalation of mercury(0) vapor. Signs and symptoms develop within hours and include weakness, myalgias, chills, fever, nausea, vomiting, diarrhea, dyspnea, cough, and chest pain [5]. Pulmonary toxicity may lead to interstitial pneumonitis with severe compromise of respiratory function. Unless fatal, recovery is usually complete, although it can be complicated by residual interstitial fibrosis.
Chronic effects. Neurologic effects are the most serious aspect of chronic exposure. With repeated exposure to mercury(0) vapor, signs and symptoms include gingivitis, stomatitis, increased salivation, fatigue, insomnia, anorexia, and renal damage [5,17]. Neurologic abnormalities can affect three general areas: (a) the motor system, (b) intellectual capacity, and (c) emotional state [18]. Motor system effects are characterized primarily by fine tremor of the extremities, weakness in the limbs, and impaired motor speed. Aspects of intellectual capacity most affected are short-term verbal and spatial memory. Impairments in emotional state can produce anxiety, depression, and avoidance. Collectively, these neurologic symptoms have been termed ‘erethism.’ The single most prominent neurologic abnormality seen with chronic exposure is tremor. Exposure-related neurological dysfunction is often reversible, although some features may be long-lasting.
Methylmercury latency. In contrast to the rapid response to mercury(0) vapor, high doses of methylmercury show a latent period of months between exposure and the onset of clinical symptoms [7,8]. Symptoms include paresthesia, ataxia, dysarthria, and hearing loss. There is little ambiguity in identifying high-dose exposure when blood specimens are collected, since mercury will be markedly elevated [7]. This is not the case with lower doses, however, and low-level chronic exposure can be associated with latency periods of years. In animal studies, adverse effects are mild and consist mainly of impaired dexterity. The developing fetus is particularly sensitive and intrauterine exposure can result is permanent disabilities.
Low-dose risks. When considering low-dose mercury exposure, it is useful to put risks into an appropriate context. Consider, for example, a report of increased risk of myocardial infarction (MI) associated with chronic, low-dose mercury [19]. Study patients with MI had significantly higher toenail mercury levels, but also had higher body-mass index and lower high-density lipoprotein cholesterol (HDL). And they were more likely to have hypertension, to be diabetic, to smoke, and to have a family history of MI. In other words, low-dose mercury is a risk factor similar in magnitude to other common risks such as being overweight. Other studies have not found an association between mercury and heart disease [20], emphasizing that the risk of low-dose exposure is modest. Such modest risk factors are important public health issues, but the clinical concern should be kept at an appropriate level.
Dental amalgams. Dental amalgams are a common source of low-level mercury exposure in patients. (For dental health care workers, amalgam formulation and manipulation represents a potentially higher level of exposure. Mercury hygiene guidelines have been issued by the American Dental Association [21].) Mercury(0) is the principal component of amalgam, usually accounting for about 50% by weight. Other metals include silver, copper, tin, and zinc. In general, patients with amalgam fillings show a small but statistically significant increase in blood and urine mercury levels. The median blood mercury concentration in 239 patients with amalgam fillings was 6.2 µg/L (25–75 percentile 4.0–8.0, maximum 22.1) versus 5.3 µg/L (2.0–8.0, 16.1) for 36 patients without amalgam fillings [22].
Adverse reactions to dental amalgams are infrequent [22]. The majority of evidence does not support the contention that amalgams contribute to amyotrophic lateral sclerosis, Alzheimer’s disease, multiple sclerosis, Parkinson’s disease, or similar degenerative disorders [8]. In contrast, contact hypersensitivity is an uncommon but well-recognized adverse reaction [23,24]. Its presentation is often characterized by lichen planus of the oral mucosa adjacent to amalgam restorations [24].
Some authors advocate the removal of dental amalgams in symptomatic patients when mercury patch testing is positive [24]; chelation challenge tests are not useful for diagnosis [25]. In a Norwegian study of patients referred for symptoms attributed to dental materials, patch testing was positive to mercury in 6% (11 of 181); reactions to at least one allergen were also seen in 28% to nickel, 23% to gold, 14% to cobalt, 9% to palladium, and 8% to components of resin-based dental materials [22]. When mercury is responsible, remission is expected about 3 months after the last amalgam filling is removed [24].
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Patient Factors |
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TopAbstractIntroductionNomenclature and Basic...Routes of ExposureDosePatient FactorsMetabolismPublished ReportsEvaluating Mercury ResultsReferences |
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Acrodynia. An example of mercury sensitivity is seen with acrodynia, also known as ‘pink disease’ (see Reports #15, #16 and #17). Acrodynia is primarily a disease of children but it can also occur in adults. Although rare at the present time, acrodynia was a common disease in the first half of the twentieth century when exposures to mercury-containing products were widespread. Warkany [27] estimated that for every 500 children exposed to mercury, only 1 developed the disorder. In acrodynia and similar disorders, it is impossible to differentiate between affected and unaffected individuals on the basis of blood and urine mercury concentrations, and diagnostic confirmation requires an appropriate response to the cessation of mercury exposure.
Immune-based reactions. Allergic reactions such as contact dermatitis can be caused by exposure to mercury, as well as to other metals such as nickel, cobalt, chromium, and copper [28]. Allergic-type reactions include tattoo reactions associated with mercury(II) sulfide [16,29], cutaneous granulomas caused by mercury(0) [16], and lichen planus of the oral mucosa caused by dental amalgams [23,24]. Patch testing has been used to confirm a diagnosis of contact allergy [28], although the usefulness of this approach has been questioned [22,29].
Mercury can induce membranous glomerulonephritis in rare individuals (see Report #12) [30]. This is an autoimmune disorder and related conditions include a scleroderma-like disorder and the induction of antinuclear antibodies [31]. Exposures to metals such as mercury and gold in experimental animals lead to disorders similar to that observed in humans. Studies of inbred mice and rats showed that a few strains are susceptible to the autoimmune effects, whereas the majority of inbred strains are resistant. These findings emphasize the genetic factors in metal-associated autoimmunity.
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Metabolism |
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and discussed below. Inorganic forms follow a similar metabolic path, while organic compounds show more complexity. In general, mercury undergoes relatively little bioaccumulation in humans [32].
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Mercury(0). With inhalation, about 80% of mercury(0) vapor is retained in the body. Dissolved vapor accumulates in the red blood cells and is subsequently carried to all tissues. Because it crosses the blood-brain barrier and the placenta, exposure can be associated with neurologic abnormalities [8]. Upon entering cells, mercury(0) is oxidized to mercury(II) with a half-life of about 2 days, and thereafter behaves like the +2 oxidation state. The highest tissue accumulation for mercury(0) remains the kidney, where it is deposited as mercury(II).
After 3 days of exposure to mercury(0) vapor in 8 adult males, blood mercury showed a half-life of 3.1 days (95% CI 2.5–4.0) for a fast phase and 18 days (CI 11–42) for a slow phase [33]. The fast phase corresponds to the redistribution of mercury to the kidneys and other tissues, whereas the slow phase is related to the fecal loss of mercury(II). Median peak urine excretion occurred 19 days after exposure and thereafter showed a median half-life of 40 days (CI 35–78). The peak corresponds to the maximum kidney accumulation. In contrast to brief contact, years of occupational exposure in 7 adults produced a longer average half-life in urine of 90 days (range 69–109) [34].
The 2-compartment model described above for blood mercury can be approximated with a 1-compartment model using a half-life (
) of 5 days [33], and the equation N = No 0.5t/, where No is blood mercury at time zero, N is at time t, and t is time in days.
Methylmercury ion. About 95% of methylmercury in foodstuffs is absorbed in the gastrointestinal tract and transported to the liver [8]. Methylmercury then undergoes an enterohepatic cycle with excretion in the bile, reabsorption in the GI tract, and return by portal circulation to the liver. A small portion is converted by intestinal flora to mercury(II) which is reabsorbed to a limited extent. Thus, most methyl-mercury is eliminated by demethylation and excretion of inorganic mercury(II) in the feces. After a single intravenous dose, the average half-life of methylmercury in blood was 44 days (range 32–60) in 7 adult men [35]. About 1.6% (range 1.3–2.1) was excreted daily in the feces. In the blood, methylmercury ion concentrates in the red cells at about 20 times that in plasma.
In the body, methylmercury is present largely as water soluble complexes with sulfhydryl compounds such as cysteine [8]. Transport across cell membranes proceeds through specific mechanisms such as the large neutral amino acid carrier, and methylmercury complexes cross the blood-brain barrier and the placenta. Less than 10% of methylmercury in blood is normally excreted in urine, although more would presumably be excreted if the kidney tubules were not reabsorbing amino acids appropriately. N-acetylcysteine (mucomyst) can markedly increase urinary excretion and appears to be a good therapeutic agent for use in methyl-mercury poisoning when started early after exposure [8,36,37].
Thimerosal and ethylmercury ion. Sodium ethylmercury thiosalicylate (proprietary names include thimerosal, thiomersal, methiolate sodium, and merthiolate) is a water-soluble compound used as a preservative [38]. It is added to many commercial products of human plasma, immunoglobulins, and vaccines, usually to a final concentration about 10 mg/L [39]. Toxicity is generally low, although allergic reactions occur, and symptomatic and fatal poisonings have been reported.
Thimerosal rapidly breaks down in the body to release the ethylmercury ion (CH3CH2-Hg+). Ethylmercury appears to be less toxic than methyl-mercury in part because metabolism is more rapid [38]. The blood half-life in adults is about 18 days. Low dose ethylmercury derived from thimerosal in vaccines had a blood half-life of 7 days (95% CI 4–10) in 40 full-term infants [40].
Phenylmercury ion. The carbon-mercury bond in the phenylmercury ion (C6H5-Hg+) is relatively weak and rapidly breaks down to release inorganic mercury(II). After inhalation of volatile phenyl mercury acetate, mercury(II) is released and follows the kinetics of the +2 oxidation state [41].
Merbromin. Merbromin (mercurochrome) is an organic mercury compound that was formerly widely used as a topical antiseptic for minor skin injuries. Accidental ingestion is usually associated with minimal toxicity. Absorption through normal skin in negligible but absorption through an omphalocele is described in Report #21 [42]. Its metabolism is determined by two characteristics: (a) merbromin is freely soluble in water and (b) the compound remains essentially intact. Because of these characteristics, merbromin is rapidly cleared in the urine. Compounds that share these characteristics may be expected to behave similarly.
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Published Reports |
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TopAbstractIntroductionNomenclature and Basic...Routes of ExposureDosePatient FactorsMetabolismPublished ReportsEvaluating Mercury ResultsReferences |
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and described briefly below (comments by the author are in parentheses). The literature review helps to emphasize that there is no clear correlation between patient symptoms and mercury concentrations in blood and urine. It is also evident that mistakes in units and concentrations are not uncommon in the mercury literature; see Report #5 [43], Report #15 [44], and Weinstein [45] for examples. Since such mistakes are more likely to occur when an analyte is unfamiliar and the magnitude of a typical result is unknown, a literature review is also useful to characterize the range of expected results. One aspect that may be obscured by the literature is that cases involving benign outcomes are probably more frequent than the dramatic presentations that tend to reach print.
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Report #1: acute ingestion fatal on day 6. Three hr after ingesting 7 g of mercury(II) chloride, a 23-yr-old female chemistry student presented with abdominal pain [11]. Gastric lavage produced bloodstained fluid. Her condition deteriorated rapidly with hypotension, respiratory failure, rectal bleeding, and renal failure. Initial blood mercury was 10,000 µg/L. Treatment included chelation and dialysis. Hypotension remained severe even with fluid and pressor support, presumably from intra-abdominal fluid shifts and leaky capillary syndrome. Serial X-rays showed progressive adult respiratory distress syndrome and on day 6 she suffered fatal cardiorespiratory arrest. (Report illustrates progression of massive mercury(II) ingestion.)
Report #2: acute ingestion discharged on day 50. Two hr after ingesting 1 g of mercury(II) sulfate powder, a 40-yr-old male developed a burning sensation in his throat [47]. Shortly after, he experienced hematemesis and respiratory failure requiring intubation and ventilation. Initial blood mercury collected 3 hr after ingestion was 15,580 µg/L. Within 12 hr of ingestion, he became anuric. Treatment included chelation and continuous veno-venous hemodiafiltration. The patient developed no neurologic features and was discharged on day 50 with a normal creatinine clearance. (Report describes significant mercury(II) ingestion that responded to aggressive treatment. Because the initial blood mercury was collected before the distribution phase was complete, the degree of exposure was probably exaggerated. Neurologic features would not be expected because mercury(II) does not typically cross the blood-brain barrier.)
Report #3: acute ingestion fatal on day 28. Approximately 24 hr after ingesting unidentified pills, a 70-yr-old female presented with nausea, vomiting, cramping abdominal pain, melena, and hematemesis [48]. Creatinine was 2.8 mg/dl and hematocrit 47% on admission. Within 48 hr, creatinine was 7.5 mg/dl, hematocrit 27%, and she became anuric. Three days after ingestion, the pills were identified as containing 1.4 g of mercury(II) chloride and the blood mercury was found to be 590 µg/L. Hemodialysis and chelating agents were started at that time. Delayed treatment may have contributed to the fatal outcome 28 days after poisoning. (Report illustrates that a relatively moderate elevation of blood mercury can be associated with a fatal outcome. Using a 1-compartment model [33], blood mercury on the initial day is estimated at 760 µg/L.)
Report #4: acute ingestion discharged on day 7. About 45 min after ingesting 40 g of mercury(II) oxide, a 31-yr-old male presented with nausea, vomiting, and abdominal cramping [49]. Initial mercury was 130 µg/L in blood and 2,220 µg/L in a 24-hr urine collection. He was treated with activated charcoal, whole-bowel irrigation, and chelation. Urine output remained normal and he was asymptomatic at discharge on day 7. (Report illustrates a potentially fatal poisoning which responded to prompt treatment. Since the oxide is much less water soluble than the chloride or sulfate salts [4], mercury(II) oxide responded to intestinal evacuation and only a small fraction of the dose was absorbed.)
Report #5: acute inhalation fatal on day 23. After silver was recovered from dental amalgam in a basement workshop, all four family members living in a home died within 9 to 23 days [43]. Patient 4 was a 41-yr-old male who presented with nausea, shortness of breath, and chills. The initial chest X-ray was normal, but subsequent studies showed bilateral infiltrates consistent with adult respiratory distress syndrome. Mercury was reported as 0.8 µg/ L (4.0 nmol/L) in blood and 21 µg/L (105 nmol/L) in urine on day 5 (concentrations clearly inaccurate). Mechanical ventilation was necessary to maintain oxygenation and the patient died on day 23 following cardiac arrest. No renal or neurologic deterioration was evident clinically. On autopsy, mercury was 1,000 µg/g (5,230 nmol/g) in kidney tissue and 19 µg/g (95 nmol/g) in brain. The kidney showed focal acute tubular necrosis on microscopy. (Report illustrates progression of massive mercury(0) inhalation. Since the blood and urine mercury were inaccurate, tissue results are included to confirm that the poisonings were caused by mercury.)
Report #6: acute inhalation with recovery. Mercury(0) boiled in a kitchen pot produced a blood mercury of 152 µg/L in a 48-yr-old male 12 days after exposure [50]. The night of exposure, the patient, wife, and son all had chest pain and difficulty breathing. The following day the patient presented with swollen eyelids, itchy red spots over his body, difficulty breathing, and nausea. Mercury was not mentioned and the condition was diagnosed as an allergic reaction. A few days later, the patient developed arthralgia that became progressively more severe. Mercury exposure was considered on day 12. The patient was treated with a nonsteroidal anti-inflammatory drug and symptoms resolved about 3 weeks after the initial event. (Report illustrates progression of symptoms associated with a moderate degree of mercury(0) inhalation. Assuming a 1-compartment model [33], blood mercury is estimated at 800 µg/L on the initial day.)
Report #7: acute inhalation at low dose. After a brief occupational exposure to low dose mercury(0) vapor, blood mercury was 85 µg/L (425 nmol/L) in an adult male described as subject 1 [33]. Random urine mercury was 32 µg/g (18.2 nmol/mmol) on day 14. (Report describes kinetics of low-dose exposure with multiple specimens collected over time.)
Report #8: subacute inhalation in a community. Several liters of mercury(0) were stolen by teenagers who played with it and took it home [51]. A 15-yr-old male (patient 1) showed a blood mercury of 329 µg/L on day 8, although exposure was probably ongoing. He was hospitalized and treated with DMPS (no symptoms were reported). Urine mercury peaked at 2,037 µg/L on day 22. A 17-yr-old male (patient 2) showed a blood mercury of 111 µg/L on day 8. He had a rash and felt unwell, but was uncooperative and not fully evaluated. A 37-yr-old female (patient 3) showed a blood mercury of 178 µg/L on day 15, although exposure probably occurred after the initial event. She was asymptomatic but treated with chelation as an out-patient. Afterwards, she required hospitalization for paresthesias, tremor, and flu-like symptoms, probably due to side-effects of chelation. (Report describes several individuals with moderate, short-term exposure to mercury(0) inhalation, and is an example of treating based on laboratory values rather than patient symptoms.)
Report #9: chronic inhalation with severe symptoms. A 29-yr-old Chinese male with occupational exposure to mercury(0) vapor in a lamp socket manufacturing factory (worker 1) presented with nervousness, irritability, gingivitis, blurred vision, tremor, stuttering and slurred speech, ataxic gait, and transient involuntary movement in the past 4 mo [52]. Mercury was 237 µg/L in blood and 610 µg/L in a 24-hr urine collection. No proteinuria was present and renal function appeared normal. (Report describes severe neurologic symptoms from chronic mercury(0) inhalation. Mercury(II) is the chemical form measured in blood and urine.)
Report #10: mercury(0) injection at 6 months. A 22-yr-old male attempted suicide by injecting approximately 8 g of mercury(0) into the left cubital fossa [53]. The patient presented 6 mo later complaining of an increasing lack of concentration and tremor. Radiographs showed widespread densities in the lungs, abdomen, and subcutaneous tissue of the elbow. Mercury concentration was 680 µg/L in blood and 140 µg/L in a random urine sample. Renal function and nerve conduction studies were normal. (Report describes remarkably mild symptoms for the degree of exposure; see also Report #11. Report emphasizes that liquid mercury(0) in the blood is considerably less available metabolically than dissolved mercury(0) vapor. Mercury(II) is the chemical form measured in blood and urine.)
Report #11: mercury(0) injection at 5 yr. A 41-yr-old male attempted suicide by injecting mercury(0) [15]. More than 5 yr after the incident, radiographs showed widespread opacities in the lungs, abdomen, and subcutaneous tissue at the injection site. Mercury concentration was 160 µg/L (800 nmol/ L) in blood and 470 µg/g creatinine (263 nmol/ mmol) in urine. Neurologic examination was normal and no biochemical evidence of toxicity was found. (Report illustrates that the findings in Report #10 are not unique; significant, chronic mercury exposure occurs in some individuals without the development of obvious symptoms.)
Report #12: chronic inhalation in a susceptible individual. A 47-yr-old male employee with exposure to mercury(0) vapor at a fluorescent-tube-recycling factory was admitted with nephrotic syndrome [30]. Mercury concentration was 41 µg/ L in blood and 158 µg/L in urine. Urine protein excretion was 12.3 g/d (reference limit <0.10 g/d) and renal biopsy showed membranous glomerulo-nephritis with granular IgG and C3 deposits along the glomerular basement membrane. Two yr after withdrawal from mercury exposure, urine protein excretion was 0.32 g/d. (Report illustrates an autoimmune disorder induced in a susceptible person. Although this phenomenon occurs rarely [31], most individuals would never develop membranous glomerulonephritis regardless of the type and intensity of mercury exposure.)
Report #13: chronic inhalation in a group. Chronic exposure of 89 Swedish chloralkali workers to mercury(0) vapor produced an average blood mercury concentration of 11 µg/L (55 nmol/L) with a range of 3–60 µg/L (15–299 nmol/L) [54]. In morning urine specimens, average mercury concentration was 25 µg/g creatinine(14.3 nmol/ mmol) with a range of 0.5–83 µg/g (0.3–46.9 nmol/ mmol). Kidney function [55], performance on psychometric tests, and tremor frequency were normal, although subtle central nervous system deficits were identified [56]. Self-reported symptoms and scores for tiredness, confusion, and neuroticism were significantly higher compared to the control group. (Studies describe chronic low-dose exposure in a group. Subtle symptoms are difficult to quantitate even in group studies.)
In 75 controls lacking occupational exposure, average blood mercury was 3 µg/L (15 nmol/L) with a range of 0.2–13 µg/L (1–65 nmol/L) [54]. The average morning urine mercury was 1.9 µg/g creatinine (1.1 nmol/mmol), range 0–7.6 µg/g (0–4.3 nmol/mmol). Blood mercury was best correlated with fish consumption and urine mercury was weakly correlated (r=0.54) with the number of dental amalgam surfaces. Fish and amalgam fillings were important sources of exposure among occupationally unexposed individuals, but these sources were overshadowed by occupational exposure. (Control group illustrates typical background concentrations, and the influences of fish and dental amalgams.)
Report #14: remote inhalation. Exposure to mercury(0) vapor at a chloralkali plant was not associated with elevated urine mercury level assayed years later [32]. Urine mercury (mean ± SD) was 3.37 ± 2.51 µg/L (95% interval 0–9.0, maximum 18.2) in 24-hr collections from 119 previously exposed individuals. Mean duration of exposure was 7.0 yr and mean time since last exposure was 6.1 yr. These values were not statistically different from specimens collected from 101 workers without prior exposure. Urine mercury increased after DMSA challenge but was not significantly different in exposed versus unexposed workers. (Study illustrates that mercury does not undergo significant bio-accumulation and that chelation challenge does not add additional information. Report also illustrates a small reference interval study, keeping in mind that studies based on more individuals show wider intervals.)
Report #15: chronic inhalation in child (acrodynia). A 23-mo-old infant was well until 1 mo prior to his referral for anorexia, weight loss, and rash [44]. He perspired excessively, was irritable, had undergone a personality change, and had become progressively less active. An erythematous, papular rash developed over his trunk 2 weeks before referral; a week later erythema and peeling of the finger tips occurred. Blood pressure and catecholamine metabolites were elevated, although further evaluation for a catecholamine-secreting tumor was cancelled after mercury results became available. Mercury in blood was 43 µg/L (43 ng/mL, listed as ng/dL most likely in error) and urine was 73 µg/L (73 ng/mL). After extensive search, the source was discovered to be mercury(0) vapor from broken fluorescent light bulbs. Symptoms disappeared rapidly after discharge, and neurologic and developmental findings were normal 6 weeks later. (Report illustrates features of acrodynia. Recovery was complete, in so far as determined. Report also provides an example of confusion concerning units, and the difficult task often encountered when trying to identify the source of mercury exposure.)
Report #16: acrodynia in a teen. A 14-yr-old male complaining of back pain was discovered to have tachycardia and elevated blood pressure [57]. Subsequently a pruritic, erythematous, maculopapular rash developed with desquamation on the palms and soles. The patient began to have paroxysmal sweating with chills and tremor, became increasingly irritable, and lost weight. A diagnosis of pheochromocytoma appeared to be confirmed by increased basal plasma and urinary catecholamines with no evidence of clonidine suppression, although no adrenal or extra-adrenal tumor could be identified. His condition deteriorated and he began to have hallucinations. At a third review of history and in response to a direct question, he admitted playing with mercury(0) at home. Mercury concentration was 22 µg/L (110 nmol/L) in blood and 80 µg/L (400 nmol/L) in urine. The home required extensive cleaning to prevent further exposure. (Report describes acrodynia in a slightly older individual. Lower blood mercury compared to Report #15 could reflect less exposure over the previous few days or could reflect measurement in a different laboratory.)
Report #17: acrodynia with ‘normal’ mercury. An 11-mo-old girl was admitted because of drowsiness, malaise, and anorexia [58]. She had been well until 6 weeks before, when she lost her appetite, began sweating profusely, and stopped crawling or standing up. On examination, she had a generalized pruritic rash, and swollen, red hands and feet with desquamation. After a 6-yr-old sister presented with less severe symptoms, the mother reported mercury from a broken thermometer had been dropped on the carpet in the children’s room 2 weeks before symptoms started. Urine mercury in the 11-mo-old was 12.6 µg/L, slightly above the reference limit of < 10 µg/L. After 3 mo of DMSA treatment, the symptoms had disappeared and urine mercury was <1 µg/L. Several months later, both children were in good health. (Report emphasizes that mercury can appear virtually normal in acrodynia. Although not needed for diagnosis, blood mercury analysis would have added supportive information.)
Report #18: fatal dimethylmercury with latent onset. A 48-yr-old chemistry professor was admitted with 5 days of progressive deterioration in balance, gait, and speech [7]. Examination showed moderate upper-extremity dysmetria (voluntary muscle movement overreaching or falling short of the intended goal), dystaxic handwriting, a widely based gait, and ‘scanning speech’ (speech with syllables separated by pauses). While working in a hood 5 mo previously (154 days before the onset of symptoms), the patient reported accidentally spilling several drops of dimethylmercury from the tip of a pipet onto the dorsum of her latex-gloved hand. Blood mercury was 4,000 µg/L and urine 234 µg/L on admission. The patient’s neurologic deterioration continued and she died 298 days after exposure. (Report describes exposure to an extremely toxic form of organic mercury with a long latent period; compare to Report #19.)
Report #19: acute dimethylmercury ingestion. A 20-yr-old male ingested several gulps of a fungicide containing ‘methylmercury’ [37]. (Methylmercury in this context refers to dimethylmercury [6]). Blood mercury was 2,800 µg/L at 2 hr after ingestion and declined to less than half that value at 12 hr; the rapid decline corresponded to the distribution phase during which the blood concentration is dispersed to tissues. Chelation was started 4–5 hr after the episode and hemodialysis with N-acetylcysteine infusion started at 1.5 days. Neurologic examination remained normal at 4 days, 6 weeks, and 1 yr. (Report illustrates prompt treatment of dimethyl-mercury poisoning; compare to Report #18. Dimethylmercury poisoning is usually not recognized until symptoms develop, at which point treatment is ineffective.)
Report #20: acute thimerosal ingestion. After drinking an aqueous solution containing 5 g of thiomersal, a 44-yr-old male developed nausea and vomiting [39]. Blood mercury was 14,000 µg/L at 4 hr after ingestion and 84 µg/L on day 19. Urine mercury was 10,700 µg/L on day 3. DMPS and DMSA did not increase mercury excretion. Polyuric acute renal failure began on day 1 with a maximum proteinuria of 9.4 g/d on day 14. Gingivitis and a maculopapulous rash developed on day 4, poly-neuropathy on day 6, and delirium on day 11 progressing to coma. Neurologic symptoms improved after day 19 and renal function returned to normal by day 40. The patient subsequently recovered completely. (Report illustrates progression of thimerosal poisoning. Thiomersal releases ethylmercury ion which is cleared rapidly relative to methylmercury ion.)
Report #21: acute merbromin exposure. A 3,498 g newborn with a large omphalocele was treated with topical 2% merbromin twice daily on days 5 through 10 [42]. Blood mercury was 252 µg/L on day 9 and 1.0 µg/L on day 15. Urine mercury was 1,105 µg/L on day 10 and 270 µg/L on day 11. The newborn developed no symptoms and received no treatment for mercury exposure, although similar exposures have been reported to result in symptoms and fatalities. (Report illustrates rapid clearance of merbromin relative to other organic forms.)
Report #22: rash from dietary methylmercury. A characteristic rash in 11 adults was associated with modest blood mercury elevations from seafood diets [59]. The rash consisted of 1–2 mm nonpruritic, discrete, flesh-colored or slightly erythematous papules especially on the palms, and occasionally on the soles of the feet and the arms and trunk. Initial blood mercury concentrations were 6–19 µg/L (29.9–94.7 nmol/L). Treatment lasted from 1 to 6 mo, and consisted of a seafood-free diet or diet with DMSA chelation. Blood mercury levels decreased and eruptions cleared in all 11 patients. (Study illustrates mild symptoms in sensitive individuals.)
Report #23: sea mammal diet. Among 492 Inuit adults living in the Canadian arctic, blood mercury concentration averaged 16 µg/L (79.6 nmol/L) with a range of 0.8–112 µg/L (4–560 nmol/L) [60]. Mercury was primarily methylmercury and was correlated with sea mammal consumption. (Study illustrates a probable extreme of dietary exposure.)
Report #24: background. Among 106 elderly individuals in Sweden, blood mercury concentrations averaged 3.4 µg/L (17 nmol/L) [61]. The range of blood mercury was 0.4–16 µg/L (2–80 nmol/L) with 5 outliers >5.6 µg/L (>28 nmol/L) that were excluded from the analysis. No relation was found between blood mercury level and cognitive function or blood pressure. (Report illustrates a typical blood mercury distribution; mercury outliers are common in population studies. Study illustrates a common problem– mismatch between the data collected and the information sought; the short half-life of blood mercury makes it unlikely to be correlated with long-term toxicity.)
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Evaluating Mercury Results |
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When there is sufficient motivation to evaluate a patient for mercury toxicity, both blood and urine are often worth collecting. Even when investigating an issue such as dietary methylmercury, where methylmercury will not typically be found in urine, the urine specimen may provide additional information such as background exposure to other mercury species. Confidence in the interpretation of mercury concentrations increases when the results are concordant among the specimen types and specimens collected at different times.
Preanalytic specimen collection. Since mercury tends to accumulate in red blood cells, whole blood specimens are generally analyzed rather than serum [62]. Accurate estimation of blood mercury from serum mercury is difficult, since it depends on the mercury species involved and the time elapsed since exposure. The preferred collection device is a vacutainer-style evacuated blood collection tube for trace elements (royal blue-top) with EDTA anticoagulant, although routine EDTA tubes (lavender-top) are probably adequate in most cases. Heparin is a suitable anticoagulant when the specimen is analyzed within 2–3 days, but the formation of microclots can render mercury analysis less reproducible after that time. Blood specimens that contain visible clots are obviously inhomogeneous and are impossible to sample adequately. Any indication that a collection tube was opened prior to analysis is a risk factor for contamination.
Opinions differ as to what is an appropriate urine specimen. A 24-hr urine collection is regarded as superior [62] but it is less convenient and more expensive, and entails greater opportunity for collection problems. A random urine specimen is adequate for most purposes [63], and a plastic, single-use urine cup with screw-on lid is an appropriate container. Assay of urine creatinine or a similar marker can be used to judge if a specimen is excessively dilute or concentrated; the World Health Organization’s guidelines for suitable urine creatinine levels are >30 mg/dl and <300 mg/dl [64]. Collection from a catheterized patient is a risk factor for mercury contamination, as is any other indication that the urine specimen has been in contact with more than a minimum number of surfaces. Collection at a worksite is a major risk factor. Addition of ultrapure acid to maximize mercury solubility may be needed when mercury concentrations are low and small differences are important, although the addition may represent another opportunity for contamination rather than an improvement in specimen quality.
For 24-hr urine collections, the tendency for incomplete or excess collections can be partially evaluated by examining total volume and creatinine. Inaccurate measurement of the total volume can be an unrecognized source of error. Collections >2 L (ie, those received in more than 1 container) are suspect for: (a) inappropriate aliquoting if not from a single container that holds the entire well-mixed specimen, or (b) potential for contamination.
Analytic issues. Adequate analysis of mercury concentrations in blood or urine requires mass spectrometry, atomic absorption, neutron activation, or a similar instrumental method. A limit of detection of 0.5 µg/L and a CV of 10% at 8.0 µg/L are characteristic of assays from carefully conducted research studies [61], although this level of performance is usually neither required or achieved in routine practice. Acceptable results are most likely to come from laboratories that participate in an interlaboratory comparison program for mercury assays in blood and urine, such as that offered by the Centre de Toxicologie du Québec (www.ctq.qc.ca). Even among such laboratories, however, assays of blood mercury in a specimen (M03-03) with a target concentration of 16 µg/L (78 nmol/L) can show a CV of 83% [65].
In clinical laboratories, mercury levels in blood and urine are usually determined as total mercury, without regard to the chemical forms that may be present. If there is concern about an unusual organic mercury compound, the assay may need scrutiny to ensure that it has been validated for that compound. Mercury speciation, available from a few reference laboratories, is usually limited to differentiating between the common inorganic and organic forms.
Elapsed time. Mercury results are obviously influenced by the time that has elapsed between the individual’s exposure and specimen collection. As a first approximation, blood mercury concentration reflects more recent exposure and urine mercury concentration is indicative of chronic, longer-term exposure. Concordance between results and the metabolic pattern is an important aspect of evaluation. A clue that methylmercury may be involved is when blood mercury is significantly elevated but urine mercury is relatively normal.
During acute exposure, the distribution phase represents rapid uptake before tissue equilibration [39]. Sampling early in an acute event may exaggerate the degree of exposure (see Reports #2 and #20). Urine mercury concentrations tend to underestimate acute exposure until the mercury excretion peaks at about 2–4 weeks. Since urine mercury has a longer half-life, it is more useful for evaluation of chronic exposure. When sufficient time has elapsed, both blood and urine mercury return to background concentrations [32] unless further exposure has occurred.
Reference intervals.
A reference interval is a measure of the mercury distribution in the population studied and is unrelated to the point at which toxicity develops. Thus, reference intervals are of limited use for interpreting analytes such as mercury. A commonly used reference interval for blood mercury is 0.6–59.0 µg/L [62], although this is much higher than the background ranges listed in Table 2
for Reports #13.1 and #24. Clear signs of mercury toxicity develop in most individuals only at some point much higher than the upper reference limit, although acrodynia is an example of a disorder that can occur within reference intervals.
Instead of a population-based reference interval, it may be preferable to select a recommended limit based on public health concerns. An example of this is the recommendation by the Environmental Protection Agency that blood mercury levels be <5.8 µg/L for women who are pregnant or who intend to become pregnant [66]. This is based on the potential danger of methylmercury to the developing fetus and is intended to be well below the concentration at which fetal effects are expected to occur.
Biologic markers. Additional laboratory tests can be employed to look for signs of mercury toxicity. Analytes in this category include urine porphyrins [67] and urine proteins such as albumin, ß2-microglobulin, and N-acetyl-ß-D-glucosaminidase (NAG) [55]. Although elevations of such analytes support the contention that mercury toxicity is present, such markers are general indicators and other causes cannot be excluded. These tests, however, have the advantage of offering objective information from the same specimens provided for mercury analysis.
Urine porphyrin patterns change as early as 1–2 weeks after exposure and remain elevated longer than urine mercury [68]. Characteristic changes include elevated levels of 4- and 5-carboxylate porphyrins, and appearance of an atypical metabolite, precopro-porphyrin. Following cessation of exposure, porphyrin concentrations revert to normal levels. For dentists with subtle changes from low-level occupational exposure, urine porphyrins were easier to measure than the associated behavioral changes [69].
Elevated urine NAG is an indication of impaired function in the renal proximal tubules. Increased NAG excretion in urine has been used to monitor the toxic effects of mercury on the kidney in an occupational setting [55,70]. The NAG isoenzyme patterns in urine have also been used to monitor mercury exposure [71].
Chelation challenge tests. Some investigators have advocated chelation challenge tests to assess the body burden of mercury [72]. Others have stated that challenge tests are not useful, particularly for assessing exposures that occurred years previously [32]. Unlike lead, mercury undergoes relatively little bioaccumulation. Chelation challenge increases the amount of mercury in urine in proportion to the amount of mercury in kidney tissue. Chelation does not provide any additional information about the kidney burden or total body burden [34]. DMPS challenge was not found to be useful as a diagnostic tool in patients with symptoms reportedly caused by mercury from dental amalgam fillings [25].
Future risk. The future risk that may be posed by past exposure to mercury is a topic of interest. As a result of chronic, high dose exposure to mercury(0) vapor, an increased risk of polyneuropathy and similar neurologic disorders was seen 20 to 35 yr later [46]. Presumably, the aging process unmasked subclinical damage that occurred years earlier. This is similar to the increased risk of developing Parkinsonian syndrome years after boxing or the late progression of poliomyelitis. Clinically apparent effects were not present in most individuals years after mercury exposure and subtle abnormalities were identified only by comparing exposed individuals to unexposed controls. The most clinically significant subtle abnormality was increased tremor associated with a peak urine mercury >600 µg/L. (Urine mercury was determined by a colorimetric method in wide use at the time and can only be taken as approximate.) Cognitive function was not significantly affected. A few individuals (18 of 247) developed polyneuropathy as a result of mercury(0) exposure. The severity of peripheral involvement was comparable to that found in a random selection of diabetic subjects.
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