Mercury Toxicity

Background

Mercury in any form is poisonous, with mercury toxicity most commonly affecting the neurologic, gastrointestinal (GI) and renal organ systems. Poisoning can result from mercury vapor inhalation, mercury ingestion, mercury injection, and absorption of mercury through the skin. (See Etiology and Prognosis.)

Mercury has 3 forms: (1) elemental mercury, (2) inorganic salts, and (3) organic compounds. Perhaps the most deadly form of mercury is methylmercury. Only 2–10% of the ingested mercury is absorbed from the gut, and ingested elemental mercury is not absorbed at all; however, 90% of any methylmercury ingested is absorbed into the bloodstream from the GI tract. (See the images below.)

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This is a 1-view, abdominal, upright radiograph in a male patient who intentionally ingested 8 ounces of elemental mercury. Notice how the mercury out....

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Patient with intentional ingestion of mercury from blood pressure instrument. Note how mercury beads can be seen deposited in lung fields. Image court....

Organic mercury compounds, specifically methylmercury, are concentrated in the food chain. Fish from contaminated waters are the most common culprits. Industrial mercury pollution is often in the inorganic form, but aquatic organisms and vegetation in waterways such as rivers, lakes, and bays convert it to deadly methylmercury. Fish eat contaminated vegetation, and the mercury becomes biomagnified in the fish. Fish protein binds more than 90% of the consumed methylmercury so tightly that even the most vigorous cooking methods (eg, deep-frying, boiling, baking, pan-frying) cannot remove it. (See Etiology.)

For centuries, mercury was an essential part of many different medicines, such as diuretics, antibacterial agents, antiseptics, and laxatives. In the late 18th century, antisyphilitic agents contained mercury. It was during the 1800s that the phrase "mad as a hatter" was coined, owing to the effects of chronic mercury exposure in the hat-making industry, where the metal was used in the manufacturing process.

In 1889, Charcot, in his Clinical Lectures on Diseases of the Nervous System, attributed some rapid oscillatory tremors to mercury exposure.^[1]

In Wilson's classic textbook of neurology, published in 1940, Wilson concurred with Charcot's attribution of tremors to mercury poisoning, but also described mercury-induced cognitive impairments, such as inattention, excitement, and hallucinosis.^[2]

In 1961, researchers in Japan correlated elevated urinary mercury levels with the features of the previously mysterious Minamata disease. Before the etiology of Minamata disease was discovered, it plagued the residents around Minamata Bay in Japan with tremors, sensory loss, ataxia, and visual field constriction. (See Presentation.)^[3]

Minamata disease is an example of organic toxicity. In Minamata Bay, a factory discharged inorganic mercury into the water. The mercury was methylated by bacteria and subsequently ingested by fish. Local villagers ate the fish and began to exhibit signs of neurologic damage, such as visual loss, extremity numbness, hearing loss, and ataxia. Babies exposed to the methylmercury in utero were the most severely affected. Furthermore, because mercury was also discovered in the breast milk of the mothers, the babies' exposure continued after birth.^[4]

On January 19, 2013, The Minamata Convention on Mercury was agreed upon at the fifth session of the Intergovernmental Negotiating Committee in Geneva, Switzerland. It is a global treaty to protect human health and the environment from the adverse effects of mercury. The major highlights of the convention included a ban on new mercury mines, the phase-out of existing ones, control measures on air emissions, and the international regulation of the informal sector for artisanal and small-scale gold mining.^[4]

Mercury is still found in many industries, including in battery, thermometer, and barometer manufacturing. Mercury can also be found in fungicides used in the agricultural industry. Before 1990, paints contained mercury as an antimildew agent. In medicine, mercury is used in dental amalgams and various antiseptic agents. (See Etiology and Prognosis.)

Mercury may also be contained in some cosmetics, such as skin-lightening products. One study measured international skin-lightening products for their mercury content, focusing on products available to US consumers either online or in stores. The products were screened for mercury content using a portable x-ray fluorescence spectrometer. Of the 549 products tested, 6% contained mercury levels above 1000 ppm, and 45% contained mercury levels that exceeded 10,000 ppm. Of lightening products purchased in the United States, 3.3% were found to contain mercury in excess of 1000 ppm. According to the authors, the Food and Drug Administration limits the amount of mercury in most cosmetic products to 1 ppm.^[5]

Complications

Minamata disease has devastating neurologic consequences as a primary outcome of methyl mercury intoxication; unfortunately, these are relatively resistant to treatment. Complications include the following (see Presentation):

• Acute perioral and facial paresthesias
• Visual-field constriction
• Respiratory distress and nonspecific dermatitis
• Extremity numbness eventually appears, along with headache, fatigue, and tremor
• Ataxia and dysarthria can also be observed

Severe poisoning eventually causes the patient to lie in a mute, semirigid posture that is broken only by episodes of crying or primitive reflexive movements. (See Presentation.)

Babies exposed in utero are the most severely affected. They are affected by low birth weight, seizure disorders, profound developmental delay, incomplete visual loss (including tunnel vision) or total blindness, and hearing loss.

Neurologic damage in the form of diffuse and widespread neuronal atrophy is most severe in patients exposed in utero. Long-term studies may indicate that even prenatal exposure at low concentrations can cause subtle, but detectable, decrements in the areas of motor function, language, and memory.

Children so affected may have long-term stigmata, including motor impairment, visual loss, hearing loss, developmental delay, and seizure disorders.

Several members of the Plenary Panel on Human Health in the 12th International Conference on Mercury as a Global Pollutant held in Korea in June 2015 wrote an excellent summary article on this meeting.^[6]

• References

Etiology

Organic methylmercury toxicity and inorganic mercury toxicity show different pathologic effects. Organic methylmercury toxicity causes prominent neuronal loss and gliosis in the calcarine and parietal cortices and cerebellar folia, as seen in cases of classic Minamata disease.^[7]

Inorganic mercury causes cerebral infarctions, as well as systemic features, such as pneumonia, renal cortical necrosis, and disseminated intravascular coagulopathy. A more diffuse, direct neuronal toxicity may also exist with organic mercury, as the brain weights of patients with Minamata disease are substantially lower than those of controls.^[8]

Nevertheless, both types of exposure may blur. In monkey models of methylmercury intoxication, demethylation resulted in inorganic mercury deposition in brain cells.^[9]

Elemental mercury

Elemental mercury (Hg) is found in liquid form, which easily vaporizes at room temperature and is well absorbed (80%) through inhalation. Its lipid-soluble property allows for easy passage through the alveoli into the bloodstream and red blood cells (RBCs). Once inhaled, elemental mercury is mostly converted to an inorganic divalent or mercuric form by catalase in the erythrocytes. This inorganic form has similar properties to inorganic mercury (eg, poor lipid solubility, limited permeability to the blood-brain barrier, and excretion in feces). Small amounts of nonoxidized elemental mercury continue to persist and account for central nervous system toxicity.

Elemental mercury as a vapor has the ability to penetrate the central nervous system (CNS), where it is ionized and trapped, attributing to its significant toxic effects. Elemental mercury is not well absorbed by the GI tract; therefore, when it is ingested (eg, thermometers), it is only mildly toxic.

Inorganic mercury

Inorganic mercury toxicity occurs in several forms: metallic mercury (Hg), mercurous mercury (Hg¹⁺), or mercuric mercury (Hg²⁺). Found mostly in the mercuric salt form (eg, batteries), inorganic mercury is highly toxic and corrosive. It gains access to the body orally or dermally and is absorbed at a rate of 10% of that ingested. It has a nonuniform mode of distribution secondary to poor lipid solubility and accumulates mostly in the kidney, causing significant renal damage. Although poor lipid-solubility characteristics limit CNS penetration, slow elimination and chronic exposure allow for significant CNS accumulation of mercuric ions and subsequent toxicity. Long-term dermal exposure to inorganic mercury may also lead to toxicity.

Excretion of inorganic mercury, as with organic mercury, is mostly through feces. Renal excretion of mercury is considered insufficient and contributes to its chronic exposure and accumulation within the brain, causing CNS effects.

Organic mercury

Organic mercury can be found in 3 forms: aryl and short- and long-chain alkyl compounds. Organic mercurials are absorbed more completely from the GI tract than inorganic salts are; this is because of intrinsic properties, such as lipid solubility and mild corrosiveness (although organic mercury is much less corrosive than inorganic mercury).

Once absorbed, the aryl and long-chain alkyl compounds are converted to their inorganic forms and possess similar toxic properties to inorganic mercury. The short-chain alkyl mercurials (methylmercury) are readily absorbed in the GI tract (90–95%) and remain stable in their initial forms. Alkyl organic mercury has high lipid solubility and is distributed uniformly throughout the body, accumulating in the brain, kidney, liver, hair, and skin. Organic mercurials also cross the blood-brain barrier and placenta and penetrate erythrocytes, producing neurologic symptoms, teratogenic effects, and high blood to plasma ratio, respectively.

Nervous system effects

Methyl mercury exerts its most devastating effect on the CNS by causing psychiatric disturbances, ataxia, visual loss, hearing loss, and neuropathy. Neurologic damage in the form of diffuse and widespread neuronal atrophy is most severe in patients exposed in utero.

Excretion of alkyl mercury occurs mostly in the form of feces (90%), secondary to significant enterohepatic circulation. The biological half-life of methylmercury is approximately 65 days.

Mercury damages the nervous system through several potential mechanisms. Mercury binds to sulfhydryl groups and incapacitates key enzymes involved in the cellular stress response, protein repair, and oxidative damage prevention.^[10] Methylmercury disrupts the muscarinic cholinergic systems in the brainstem and occipital cortices as well.^[11]

Methylmercury also inactivates sodium-potassium adenosine triphosphatase (Na+/K+-ATPase), which leads to membrane depolarization, calcium entry, and eventual cell death.^[12] Several pathways may be simultaneously activated converging in apoptosis.^[13]

Researchers have also identified excessive excitotoxins and dysregulation of the nitric oxide system in rodents exposed to methylmercury.^[14] Methylmercury can also induce brain edema, and this may produce sulcal artery compression and consequent ischemia, which may account, at least in part, for the calcarine and parietal cell loss and gliosis.

Furthermore, methylmercury may sequester the element selenium and thereby disrupt cellular biochemical pathways that use selenium as an enzymatic cofactor. Substantial evidence suggests that supplementing selenium ameliorates or even reverses mercury toxicity in laboratory animals.^[15]

Finally, the effects of mercury may be modified by a person’s genetic milieu. For example, the interaction between mercury exposure and a genetic polymorphism in heme biosynthesis (coproporphyrinogen oxidase) yielded additive impairments on a test of visual-motor skills in dental workers,^[16] and, more recently, additive impairments were documented between urinary mercury levels and a serotonin transporter polymorphism on motor control tasks in a similar population.^[17] Furthermore, certain heat shock protein polymorphisms have been associated with symptomatic mercury toxicity compared with asymptomatic, but, similarly exposed, controls,^[18] in particular single-nucleotide polymorphisms of metallothionein (a group of heavy metal-binding proteins), have been associated with reduced hair mercury levels among dental professionals.^[19]

Renal effects

Necrosis of the proximal tubules is a common direct renal toxic effect. Unexplained renal abnormalities with neuropsychiatric disturbances should prompt the physician to consider mercury toxicity.

Sources of mercury poisoning

Causes of elemental mercury toxicity include the following:

• Thermometers
• Barometers
• Batteries
• Bronzing
• Calibration instruments
• Chlor-alkali production
• Dental amalgams
• Electroplating
• Ethnomedical practices
• Fingerprinting products
• Fluorescent and mercury lamps
• Infrared detectors
• Jewelry industry
• Manometers
• Neon lamps
• Paints
• Paper pulp production
• Photography
• Silver and gold production
• Semiconductor cells

In the United States, exposure to organic mercury is primarily through ingestion of contaminated fish. Persons who consume large amounts of seafood from contaminated waters have an increased risk of toxicity. Surveys indicate that public awareness of the risks of mercury-contaminated fish is limited.

The causes of organic mercury toxicity also include the following:

• Antiseptics
• Bactericidals
• Embalming agents
• Farming industry
• Fungicides
• Germicidal agents
• Insecticidal products
• Laundry products
• Diaper products
• Paper manufacturing
• Pathology products
• Histology products
• Seed preservation
• Wood preservatives

The causes of inorganic mercury toxicity include the following:

• Antisyphilitic agents
• Acetaldehyde production
• Chemical laboratory work
• Cosmetics
• Disinfectants
• Explosives
• Embalming
• Fur hat processing
• Ink manufacturing
• Mercury vapor lamps
• Mirror silvering
• Perfume industry
• Photography
• Spermicidal jellies
• Tattooing inks
• Taxidermy production
• Vinyl chloride production
• Wood preservation

Newer compact, energy-efficient fluorescent lights contain substantial mercury concentrations, making breakages with subsequent release a concerning source of exposure.^[20]

Products from mercury cell chlor-akali plants used in the production of high-fructose corn syrup have been shown to contain detectable levels of mercury.^[21]

Mercury-containing disk batteries are a concern because of their ability to cause corrosion and ulceration of the GI mucosa. With battery ingestion, one would expect signs of inorganic mercury exposure, such as hypersalivation and vomiting, rather than signs of organic mercury poisoning.

One major risk factor for mercury toxicity is industrial contamination. Workers employed in the manufacturing of mirrors, thermometers, fluorescent lights, and radiography machines, as well as in gold mining, are at risk for inorganic mercury poisoning. Organic mercury poisoning can occur among exposed workers in the paper and pulp industries.

New York City public health officials traced potentially toxic urinary mercury levels in residents to contaminated skin-lightening creams, which were subsequently removed from stores and embargoed.^[22] More recently, a similar exposure occurred in a Mexican-American family in California and Virginia.^[23] Others have identified renal disease secondary to mercury toxicity from such putative beautifying topicals.^[24]

Traditional religious and healing practices are risk factors for mercury exposure. Mercury has been identified as a contaminant in Chinese herbal balls,^[25] and it has been used in the Santeria religion, as well as in Tibetan medicine.^[26] Indeed, spectrophotometric measurements of mercury vapor concentrations were elevated in New Jersey buildings located near "botanicas" in a primarily Latino community, compared with a control community.^[27] Furthermore, of herbal Ayurvedic preparations, 20% were found to contain high levels of mercury.^[28]

Even the mercury vapors from dental amalgam have been of concern as a possible, although controversial, source of exposure among dental workers and the general population. A study of 1663 veterans used a wide battery of noncognitive tests and found no clinically evident deficits associated with amalgam exposure. However, a subclinical decrement in vibration as measured by an automated device correlated with amalgam exposure and accounted for 15% of the variance in a multiple regression model.^{[29, 30]} Furthermore, no consistent correlation could be established between urinary mercury levels and nerve conduction parameters among dental professionals.^[31]

Two randomized studies of a total of 1041 children aged 6–10 years whose dental caries were treated with either amalgam or resin composite fillings showed no group differences on extensive batteries of neuropsychological tests after 5–7 years of follow-up.^{[32, 33]} After an exhaustive investigation and review of the evidence, including the form of mercury in question, the route of exposure, and the dose, the Public Health Service concluded that dental amalgams do not pose a serious health risk.^{[30, 34]}

Intentional self-poisoning with oral or injected inorganic mercury has been described, with outcomes varying from coma and death despite heroic efforts^[35] to surprisingly scant clinical sequelae in the setting of persistently elevated blood mercury levels 5 years after the attempt.^[36]

A very controversial source of organic mercury exposure is thimerosal, a preservative used in vaccines to prevent bacterial contamination. The most commonly used vaccines that contain thimerosal are for diphtheria-tetanus-whole cell pertussis (DTP), Haemophilus influenzae (HIB), and hepatitis B. However, no definite link between this small amount of mercury and any known disease has been found. Nonetheless, concerns over mercury content in vaccine have led to the increased availability of mercury-free vaccines.^{[37, 38, 39]}

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Epidemiology

Occurrence in the United States

The 2013 Annual Report of the American Association of Poison Control Centers' National Poison Data System documented about 1300 single exposures to mercury or compounds containing mercury. Of these, 109 were in children younger than 6 years and 673 were in persons older than 19 years. Overall, 19 individuals were reported to have moderate effects, 5 had major effects, and none died as a result of mercury exposure.^[40]

International occurrence

Worldwide, outbreaks of methylmercury intoxication are sporadic. Minamata Bay in Japan was involved in the first and most famous epidemic, but not the largest. In the early 1970s, one of the most severe mass poisonings in history occurred in Iraq, when nearly 95,000 tons of seed grains treated with a methylmercury-based fungicide were accidentally baked into bread for human consumption.^[41] More than 6000 individuals were hospitalized, and hundreds died. Many were hospitalized for weeks before methylmercury intoxication was correctly diagnosed.

Mercury mining areas in China have also contributed to cases of methylmercury poisoning through the ingestion of rice grown in contaminated soil.^[42] Small-scale gold mining in developing countries has also produced mercury toxicity.^[43]

Age-related demographics

Toxicity probably affects developing fetuses and children preferentially compared with other age groups, but even on this point, the data are incomplete. Prenatal exposure through maternal consumption of predominantly fish and whale meat has been shown to impair development among children in the Faroe Islands, while maternal mercury exposure from fish consumption alone in the Seychelles did not result in significant developmental problems among children prenatally exposed.^{[44, 45]} The protective effects of the naturally selenium-enriched fish diet of the Seychelles population has been proposed to explain this effect.^[15]

In a case of a family exposed to methylmercury through the ingestion of contaminated pork, the more severe clinical manifestations were found in the younger children.^[46]

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Prognosis

Recovery from mercury poisoning is variable. Acute fulminant intoxication with methylmercury resulted in coma and death in the Minamata catastrophe. Delayed toxicity can also occur, as in a fatal case in which symptoms developed only several months following absorption of dimethylmercury through the skin.^[47] Mercury vapors also can result in acute neurologic and generalized symptoms.

While the cognitive and emotional sequelae of mercury exposure, at least in adults, may diminish with time, tremors and neuropathic changes have been reported to persist for decades after inorganic mercury exposure. For example, among 104 workers examined 30 years following inorganic mercury exposure, the presence of resting tremors correlated significantly with prior cumulative mercury exposure.^{[48, 49]}

Outcome in mercury toxicity depends on the form of the mercury compound and the severity of exposure. Mild exposure to inorganic (ie, elemental, mercuric salt) and organic compounds can result in a complete recovery. Fatality is usually the result of severe exposure to mercuric salt. Most organic mercury exposures leave a neurologic sequela. Minimal dermal exposure to dimethylmercury has resulted in progressive neurologic deterioration and death, with initial symptoms delayed for several months.

All forms of mercury are toxic to a fetus, but methylmercury most readily passes through the placenta. Even with an asymptomatic patient, maternal exposure can lead to spontaneous abortion or retardation.

Individuals who need to be admitted to the hospital include the following:

• Individuals who ingested (or are thought to have ingested) mercury salts
• Individuals thought to have elemental mercury inhalation and have pulmonary injury
• Individuals who require intensive chelating therapy

Minamata disease

Once the neurologic sequelae of Minamata disease are evident, the damage is irreversible, and severe intoxications have been fatal. However, the damage may be minimized if detected early enough. Effects of long-term exposure are only now being fully recognized. Most survivors of Minamata disease have chronic neuropathologic conditions such as the following:

• Ataxia
• Visual-field loss
• Psychiatric disturbances
• Sensory loss
• Chronic paresthesias

Compared with other patients, babies exposed to Minamata disease in utero have a more dismal prognosis. Their sequelae include the following:

• Severe developmental delay
• Low birth weight
• Persistent cognitive impairment

Of the original 121 individuals from Minamata Bay who were affected, nearly one third died shortly after their initial presentation. Subsequent investigations since the late 20th century resulted in the identification of more than 2000 additional patients who were affected by chronic sequelae of Minamata disease.

Dietary consumption of mercury

The primary source of environmental exposure to mercury in the general population is through the consumption of contaminated fish.^[50] Fish consumption has clear health benefits, and the risk posed by mercury exposure is currently speculative. The fetal brain is more susceptible to mercury-induced damage than that of an adult. As a result of this data, the Environmental Protection Agency (EPA) reduced the allowable intake of methylmercury from 0.5 mcg to 0.1 mcg of mercury per kilogram per day, which is lower than the amount allowable according to other regulatory agencies.^[51]

The EPA guideline is derived from reports of subtle and small neuropsychological changes in children in a study in the Faeroe Islands; the children’s exposure was mainly from whale consumption.^[52] A similar study in the Seychelles found no adverse effects from fish consumption alone.^[53]

The Food and Drug Administration (FDA) has recommended that pregnant women, breastfeeding mothers, and young children avoid eating fish with a high mercury content (>1 ppm), such as shark, swordfish, tilefish, and king mackerel. This also includes fresh and frozen tuna (mercury content between 0.5 ppm and 1.5 ppm). Canned tuna has exhibited variable mercury concentrations, with one study finding that 55% of cans contained mercury levels greater than 1 ppm, with white tuna demonstrating higher levels than light tuna.^[54]

From a nonprofessional perspective, this translates into a weekly consumption of 1 can (198g, or 7oz) of tuna for an adult.^[55] Rather than ban the sale of these species, Health Canada recommends that they be consumed no more than once per week or once per month by children and by women of childbearing age.^[56] Mercury levels in freshwater fish vary, but, in general, bass, pike, muskellunge, and walleye have high levels of mercury and should be eaten in moderation. Provincial guidelines for sport fish often mirror federal seafood recommendations.^[57]

Inhalation exposure

Acute exposure caused by inhaled elemental mercury can lead to pulmonary symptoms. Initial signs and symptoms, such as fever, chills, shortness of breath, metallic taste, and pleuritic chest pain. Other possible symptoms include stomatitis, lethargy, confusion, and vomiting. In addition, elemental mercury can also be injected, causing a life-threatening pulmonary embolism.

Recovery is usually without sequela, but pulmonary complications of inhaled toxicity may include interstitial emphysema, pneumatocele, pneumothorax, pneumomediastinum, and interstitial fibrosis. Fatal acute respiratory distress syndrome (ARDS) has been reported following elemental mercury inhalation.

Vaccine-associated exposure

Thimerosal is a mercury-containing preservative used in some vaccines and other products since the 1930s. No harmful effects have been reported from thimerosal at doses used in vaccines, except for minor reactions, such as redness and swelling at the injection site. However, in July 1999, the Public Health Service agencies, the American Academy of Pediatrics, and vaccine manufacturers agreed that thimerosal should be reduced or eliminated in vaccines as a precautionary measure. Today, with the exception of some influenza vaccines, none of the vaccines used in the United States to protect preschool children against 12 infectious diseases contain thimerosal as a preservative.^[58]

Exposure to mercury has been suggested to contribute to the development of autism in children. Although the mechanism for this disorder has many hypotheses, no evidence has confirmed a causal relationship between mercury exposure and the development of autism. In fact, in one study, the discontinuation of thimerosal-containing vaccines in Denmark seemed to be followed by an increase in incidence of autism.^[59]

In 2004, Immunization Safety Review Committee of the US Institute of Medicine (IOM) shifted from the position of neutrality to the conclusion that "the evidence favors rejection of a causal relationship between thimerosal-containing vaccines and autism."^[60] Since 2004, 2 cohort studies from the United Kingdom examined the relationship between thimerosal contained within vaccines and autism, and their conclusions were in agreement with the IOM that there is no causal relationship between the two.

A recommendation from the American Academy of Pediatrics and the US Public Health Service states that the use of products containing thimerosal is preferable to withholding vaccinations, which protect against diseases that represent immediate threats to infants (ie, pertussis, H influenzae). For the hepatitis B vaccine, adjustments in timing within the ranges proposed in the immunization schedule provide additional opportunities to minimize thimerosal exposure to infants. If thimerosal-free vaccine is not available, the hepatitis B virus vaccination should be initiated in infants aged 6 months.

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Patient Education

Unfortunately, a clinician can do little to prevent mercury toxicity. Public education can raise awareness about the risks associated with easily preventable sources of toxicity, such as contaminated herbal preparations or mercury thermometers.

Publicizing the amount of mercury contained in frequently eaten fish can help to reduce toxicity on a local level.

Mercury is being found more often in our household items such as fluorescent bulbs and the risk of potential exposure has increased. The need to understand proper procedure for disposing of potential exposure is critical. The EPA has outlined a clear process to dispose of accidental spill. For complete details on mercury spills with specifics related to a broken thermometer or fluorescent bulb, visit the EPA Web site.^[61]

Minamata disease typically occurs in areas in which the population depends on seafood as a dietary staple and in areas in which industrial wastes contaminate the drinking water. Educate patients about alternative food sources and about eliminating their intake of contaminated fish.

Outbreaks of methylmercury poisoning also have occurred after the introduction of fungicide-treated grain into the food supply. Neither humans nor livestock should eat seed grain treated with mercurial fungicides.

For patient education information, see the First Aid and Injuries Center, as well as Poisoning and Activated Charcoal.

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History

The diagnostic approach for patients with suspected mercury toxicity begins with a thorough history that includes occupations, hobbies, and levels of seafood intake. All toxic presentations, whether acute, chronic, or subacute, are difficult diagnoses because multiple organ systems are affected (eg, CNS, kidney, mucous membranes) and can mimic a variety of other diseases. If no such history exists, clinical suspicion can be confirmed by laboratory analysis.

The symptoms of mercury intoxication are manifold. Patients can present with complaints of numbness, tingling, hearing loss, visual difficulties, gait unsteadiness, and tremulousness, as well as emotional and cognitive difficulties. Obviously, assessing the risk of exposure, which can be acute or long term, is paramount to making a diagnosis.

Some unique features of mercury poisoning have generated their own nomenclature, as follows:

• Metal fume fever - Occurs in the acute phase of mercury vapor toxicity and is manifested by fatigue, weakness, fever, chills, dizziness, headache, abdominal cramping, dyspnea, dysuria, and ejaculatory pain
• Acrodynia - Also known as pink disease and considered to be a mercury allergy; presents with erythema of the palms and soles, edema of the hands and feet, desquamating rash, hair loss, pruritus, diaphoresis, tachycardia, hypertension, photophobia, irritability, anorexia, insomnia, poor muscle tone, and constipation or diarrhea; acrodynia does not present in everyone who is exposed to inorganic mercury, but it is an indicator of widespread disease^{[62, 63]}
• Erethism - A constellation of irritability, excitability, anxiety, insomnia, and social withdrawal; erethism traditionally is seen in the chronic phase of the inorganic mercury toxicity.

Chronic and intense, acute mercury exposure cause cutaneous and neurologic symptoms. The classic triad found in chronic toxicity is tremors, gingivitis, and erethism. Additional findings may include headache, visual disturbance (eg, tunnel vision), peripheral neuropathy, salivation, insomnia, and ataxia.

Inorganic mercury exposure

Exposure to inorganic mercury or mercuric salt occurs mainly through the oral and GI tract. Its corrosive properties account for most of the acute signs and symptoms of inorganic mercury or mercuric salt toxicity. The acute presentation can include ashen-gray mucous membranes secondary to precipitation of mercuric salts, hematochezia, vomiting, severe abdominal pain, and hypovolemic shock.

Systemic effects usually begin several hours postingestion and may last several days. These effects include metallic taste, stomatitis, gingival irritation, foul breath, loosening of teeth, and renal tubular necrosis leading to oliguria or anuria.

Organic mercury exposure

Organic mercury poisoning usually results from ingestion of contaminated food. The long-chain and aryl forms of organic mercury have similar toxic characteristics as inorganic mercury. The onset of symptoms usually is delayed (days to weeks) after exposure.

Organic mercury targets enzymes, and the depletion of these enzymes must occur before the onset of symptoms.

Symptoms related to toxicity are typically neurologic, such as the following:

• Visual disturbance - Eg, scotomata, visual field constriction
• Ataxia
• Paresthesias (early signs)
• Hearing loss
• Dysarthria
• Mental deterioration
• Muscle tremor
• Movement disorders
• Paralysis and death - With severe exposure

Organic mercury targets specific sites in the brain, including the cerebral cortex (especially the visual cortex), motor and sensory centers (precentral and postcentral cortex), the auditory center (temporal cortex), and the cerebellum.

If methyl mercury intoxication is suspected, inquire about the patient's diet, including the following:

• Amount of fish consumed
• Frequency of consumption
• Types of fish consumed
• Source of fish consumed
• Source of water supply

Also inquire about classic symptoms, including the following:

• Perioral and facial paresthesias
• Extremity numbness
• Dysarthria
• Headache
• Constriction of the visual fields
• Difficulty in hearing
• Memory loss
• Problems with walking

Methyl mercury exerts its most devastating effect on the CNS by causing the following:

• Psychiatric disturbances
• Ataxia
• Visual loss
• Hearing loss
• Neuropathy

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Physical Examination

Although no physical findings are pathognomonic for mercury toxicity, the constellation of gait ataxia, tremulousness, hearing loss, visual field constriction, dysarthria, and distal limb sensory loss, coupled with cognitive and emotional dysfunction, is suggestive. Perform a complete neurologic examination, including a detailed cerebellar examination. Perform a full visual field evaluation. (Hearing loss and visual field impairments more often occur with organic poisoning, as in Minamata disease.)

Perform abdominal and rectal examinations, with stool guaiac testing, and include documentation of a skin examination.

Distal sensory loss, uncoordinated limb movements, resting tremors, gait ataxia, and a positive Romberg sign have been described after exposure to organic and inorganic mercury. A 2004-2005 study of 197 Minamata Bay residents who were exposed to methylmercury before 1968 found 90% with sensory impairments on the bedside neurologic examination.^[64]

Cranial neuropathies are very rare, but sixth and third nerve palsies were described in a man who injected himself with subcutaneous elemental mercury.^[65]

Emotional instability and cognitive impairments can be present in both types of exposure; however, these deficits are more characteristic of acute inorganic mercury toxicity. Neuropsychological testing in these cases has revealed pronounced impairments in traditional frontal lobe domains.^[66]

Low-level organic mercury exposures have been controversial. A study of 129 residents of fishing villages in Brazil reported that higher hair mercury levels were associated in a dose-dependent manner with reduced response inhibition and manual dexterity.^[67]

In addition, elevated blood mercury levels were associated with significantly reduced visual recall but improved manual dexterity in 474 elderly people in Baltimore, Md. Other tested domains were unaffected, and because of the disparate results, these researchers concluded that study provided no "compelling evidence" that blood mercury levels influenced the neurobehavioral status of their subjects.^[68]

In 240 adults living near an abandoned chlor-alkali factory in Taiwan, those with the higher blood methylmercury levels had significantly worse memory and mental manipulation abilities than did those with lower methylmercury levels.^[69]

Nonneurologic findings include skin changes, with contact dermatitis predominating, although cutaneous hyperpigmentation and stomatitis also occur.^[70] Erythematous papules and papulovesicles, primarily on palms, have been reported to be associated with mercury toxicity attributed to seafood ingestion.^[71] Respiratory distress can occur acutely in mercury poisoning.

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Approach Considerations

History and physical examination findings consistent with mercury poisoning are helpful, but blood, urine, and (sometimes) tissue analyses are required to confirm the diagnosis of mercury intoxication (although exact toxicity levels remain undefined).

Correlations have been found between signs, symptoms, and electrophysiologic studies of subjects exposed to mercury with various statistical extrapolations of measures of exposure, such as duration of exposure, peak urinary mercury levels, and estimated cumulative mercury dose.

Whole blood mercury levels are usually less than 2 mcg/dL in unexposed individuals, although individuals with a high dietary fish intake may be an exception.

Obtain a complete blood count (CBC) and serum chemistries to assess possible anemia secondary to GI hemorrhage, to determine if renal failure is present, and to rule out electrolytic abnormalities.

In most laboratories, mercury quantification is not performed on a routine basis; therefore, contact the laboratory to verify the specific collection and precautionary protocols before blood and urinary samples are collected. Reserve neuroimaging and electrophysiologic testing for selected cases. Consider pregnancy tests in women of childbearing age.

Histology

Occasional sural nerve biopsies have been performed on patients with mercury toxicity. Two cases of inorganic mercury poisoning revealed a combination of axonal and demyelinating changes.^[72] Organic mercury toxicity in Minamata disease resulted in the preferential loss of large myelinated nerve fibers.^[73]

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Mercury Level Analysis

In the United States, based on the 2003 National Health and Nutrition Examination Survey (NHANES) data, urinary mercury levels of 5 mcg/L and blood mercury levels of 7.1 mcg/L encompassed 95% of the sample. These have been recommended as medically credible comparison levels.^[74]

Hair

While blood levels are useful for more acute exposures, long-term exposures are best reflected in hair mercury measurements. Hair has high sulfhydryl content. Mercury forms covalent bonds with sulfur and, therefore, can be found in abundance in hair samples.

Because of environmental contamination, hair measurements have been problematic with elemental mercury exposure, but methylmercury hair measurements are considered accurate.^[75] A hair value of 1.2 mcg/g encompassed 90% of the NHANES sample.^[74]

Interestingly, investigators of Minamata disease identified chronic forms of the disease in which hair mercury levels were not elevated. A delayed neurotoxic effect, with symptoms emerging after age-induced neuronal loss, was hypothesized.^[3] Similarly, some researchers have been unable to correlate the fluctuations of mercury blood levels with signs and symptoms of toxicity in mercury vapor exposure.^[76]

Blood

Methylmercury concentrates in erythrocytes; therefore, mercury levels in blood remain high in acute toxicity. When ingested by humans, methylmercury is easily absorbed and retained by the body; it has a half-life in blood of about 44 days, which makes blood tests useful measures of acute exposure.^[77]

The blood level correlation with chronic methylmercury toxicity is more variable. Methylmercury exhibits a blood-to-plasma ratio of up to 20:1, a characteristic of organic mercury. This higher ratio may be useful in determining if the patient was exposed to organic or inorganic mercurials. Aryl mercury compounds accumulate in RBCs but are metabolized to inorganic mercury more rapidly, thus, demonstrating lower blood-to-plasma ratios than those observed with methylmercury exposures.^[78]

Following high exposure to inorganic mercury salts, the blood-to-plasma ratio ranges from a high of 2:1 to 1:1. Paraesthesias are expected if blood mercury levels are higher than 20 mcg/dL.

Inorganic mercury redistributes to other body tissue; thus, its levels in the blood are accurate only after an acute ingestion. In general, blood levels of mercury are helpful for recent exposures and for determining if the toxicity is secondary to organic or inorganic mercury, but they are not useful for a guide to therapy.

Urine

Urinary mercury levels are typically less than 10-20 mcg/L. Excretion of mercury in urine is a good indicator of inorganic and elemental mercury exposure but is unreliable for organic mercury (methylmercury) because this is eliminated mostly in the feces. In cases of chronic mercury toxicity, the urinary mercury measurement may be falsely low.^[79]

No absolute correlation exists between urinary mercury levels and the onset of symptoms; however, levels higher than 300 mcg/L are associated with overt symptoms. Mercury levels in the urine also can be used to gauge the efficacy of chelation therapy, since chelated mercury is excreted primarily through the kidneys. For workers chronically exposed to mercury compounds, urinary excretion with mercury levels higher than 50 mcg/L is associated with an increased frequency of tremor.

Short-chained alkyl mercury compounds are excreted predominantly by the bile, rendering urinary measurements of these invalid.^[79]

The position of the American College of Medical Toxicology (ACMT) does not support routine practice of postchallenge urinary metal testing, due to a lack of demonstrable benefits. This practice may be harmful if applied routinely in the assessment and treatment of patients suspected of having metal poisoning.^[80]

Toenail

Toenail mercury has also been used as a measure of long-term mercury exposure, with mean levels of 0.25-0.45 mcg/g among Western samples. Toenail mercury has been correlated with fish and shellfish consumption.^{[81, 82]}

Cerebrospinal fluid

Cerebrospinal fluid (CSF) mercury concentrations have been measured with mass spectroscopy, and normal values vary widely. Nevertheless, increased CSF mercury levels have been found in workers with ongoing exposure to mercury vapors, but these CSF levels, unlike blood levels, normalize several months after such exposures have abated.^[83]

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Imaging Studies

Radiography

Obtain a flat plate radiograph of the abdomen to visualize ingested elemental mercury, which appears radiopaque. (See the images below.)

View Image

This is a 1-view, abdominal, upright radiograph in a male patient who intentionally ingested 8 ounces of elemental mercury. Notice how the mercury out....

View Image

Patient with intentional ingestion of mercury from blood pressure instrument. Note how mercury beads can be seen deposited in lung fields. Image court....

MRI

Neuroimaging is probably more helpful in excluding other diagnoses than in ruling in mercury toxicity. Nonetheless, magnetic resonance imaging (MRI) in cases of Minamata disease confirms the clinical and pathologic findings. Marked atrophy of the calcarine and parietal cortices, as well as the cerebellar folia, has been visualized.^[84]

MRI findings in one patient with inorganic mercury toxicity revealed mild cortical atrophy and T2 hyperintensities in the frontal and subcortical regions.^[85] Additionally, a 4-year-old with inorganic mercury poisoning developed transient fluid-attenuated inversion recovery (FLAIR) hyperintensities in cortical white matter during chelation therapy.^[86]

SPECT

Single-photon emission computed tomography (SPECT) demonstrated right cingulate hypermetabolism in a 38-year-old man with emotional lability and inattention following exposure to inorganic mercury.^[87]

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Electrophysiology

Electrophysiologic studies have demonstrated sensorimotor neuropathy, typically axonal, in some workers exposed to elemental mercury or mercury vapors. Workers with remote exposures, however, have exhibited only minimal conduction velocity slowing.^[88] Abnormalities have also been documented in visual-evoked potential studies among workers exposed to mercury vapors.^[76]

In the Faroe Islands, intrauterine methylmercury exposure (as determined by maternal hair and cord blood measures) was positively correlated with prolonged brainstem evoked potentials (III and V latency peaks) 14 years after initial exposure.^[89]

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Approach Considerations

Notify state and local health officials to clarify the mechanism of exposure and to institute appropriate decontamination measures, should these be necessary.

Treatment of mercury toxicity consists of removal of the patient from the source of exposure, supportive care, and chelation therapy. Patients with cognitive and emotional sequelae may require psychotropic medications.

Although laboratory studies are important, acute treatment in critical situations should be based on the patient’s history and clinical presentation, without waiting for laboratory confirmation.

Little information is available about the treatment of mercury-induced tremulousness, but initiation of empiric treatment for patients who are functionally impaired with this complication would be reasonable.

Once the neurologic consequences of Minamata disease appear, they are, unfortunately, irreversible. The goal of medical management in Minamata disease is to reduce the total body burden of mercury and minimize further damage.

Prehospital care

Prehospital management includes gathering information on the time, type, and mode of mercury exposure, as well as the following:

• Initial assessment - Airway, breathing, and circulation (ABCs)
• Oxygen
• Intravenous (IV) access
• Removal from the contaminated area

Surgical care

Surgery does not have a role in the treatment of Minamata disease; however, in other forms of mercury exposure, surgical intervention is sometimes warranted. Surgery occasionally has been employed to remove ingested mercury that has become lodged in the intestine or colon.^[90]

Surgical removal of subcutaneous deposits of self-injected elemental mercury has also been described.^[91] Early, definitive surgical excisions of the mercury deposits resulted in good outcomes with minimal toxicity.

Inpatient care

All patients in unstable condition should be admitted to an intensive care unit (ICU). After the patient is admitted, supportive measures, decontamination, and careful monitoring should be continued. In cases of inorganic mercuric salt ingestion, carefully monitor the patient's renal function.

Transfer

Serious clinical manifestations due to mercury exposure should be managed in a tertiary care facility by physicians experienced with toxicologic emergencies.

Activity

Employment and driving should be restricted if patients have significant emotional or cognitive problems.

Consultations

Consult with the regional poison control center or a medical toxicologist (certified through the American Board of Medical Toxicology and/or the American Board of Emergency Medicine) for additional information and patient care recommendations.

Follow-up

Determine follow-up care on a case-by-case basis. Obtain laboratory measurements of toxicity in patients with possible continued sources of exposure.

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Emergency Department Care

Supportive care begins with the ABCs, especially when managing the inhalation of elemental mercury and the ingestion of caustic inorganic mercury, both of which may cause the onset of airway obstruction and respiratory failure. The next step in supportive care is the removal of contaminated clothing and copious irrigation of exposed skin. Aggressive hydration may be required for acute inorganic mercury poisoning because of its caustic properties. Do not induce emesis if the compound ingested is of the caustic inorganic form.

Gastric lavage is recommended for organic ingestion, especially if the compound is observed on an abdominal radiograph series.

Activated charcoal is indicated for GI decontamination because it binds inorganic and organic mercury compounds to some extent.

Whole bowel irrigation may be used until rectal effluent is clear and void of any radiopaque material. However, its effectiveness in decreasing the GI transit time of elemental mercury is doubtful because of the high density of elemental mercury and the low density of the whole bowel irrigant solutions. Likewise, whole bowel irrigation has no adsorptive effect on any type of mercury within the GI tract.

Use chelating agents if the patient is symptomatic, if systemic absorption is anticipated, or if increased blood or urinary mercury levels are present. Chelating agents contain thiol groups, which compete with endogenous sulfhydryl groups.

Hemodialysis is used in severe cases of toxicity when renal function has declined. The ability of regular hemodialysis to filter out mercury is limited because of mercury's mode of distribution among erythrocytes and plasma. However, hemodialysis with L-cysteine compound as a chelator has been successful.

Older literature indicates that neostigmine may help motor function in methylmercury toxicity as this toxicity may lead to acetylcholine deficiency.^[92]

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Chelation

Because mercury binds to the body's ubiquitous cellular sulfhydryl groups, chelating agents should be administered early in treatment.

Chelating agents contain thiol groups, which bind to mercury. For acute, inorganic toxicity, dimercaprol (British antilewisite [BAL]) has traditionally been recommended, but oral agents are gaining prominence. Chelation with 2,3-dimercaptosuccinic acid (DMSA or succimer) has been shown to result in increased mercury excretion, compared with N -acetyl-D,L-penicillamine, in adults with acute mercury vapor exposure. DMSA is generally well tolerated and has also demonstrated efficacy in children exposed to mercury. Chelation treatment may be administered in the outpatient setting with an oral chelator, such as DMSA.^[93]

Polythiol is a nonabsorbable resin that can theoretically help in facilitating the removal of methylmercury (short chain alkyl organic mercury), which is then excreted in the bile after enterohepatic circulation.

Exchange transfusion has been used as a treatment of last resort. Because mercury-chelating agent complexes are large molecules, they may fail to be filtered out by standard hemodialysis membranes, rendering conventional hemodialysis ineffective.^[94]

Despite the increased excretion of mercury with chelating agents, chelation removes only a small portion of the body's mercury stores. Furthermore, the efficacy of chelating agents in treating neurologic complications has not been established; however, among patients with amalgam fillings, placebo responses to chelation treatment have been reported.^[95]

Finally, caution is warranted, however, as some physicians have documented initial clinical deterioration during chelation therapy.^[86]

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Diet

Seafood rich in organic mercury should of course be avoided. Predators such as sharks and tuna typically have increased mercury concentrations compared with herbivorous fishes.

In some studies, the levels of mercury in shark, swordfish, and large tuna steaks exceeded the Food and Drug Administration (FDA) safety limit of 1 part per million. However, most other fish sold in the United States have clearly lower levels of approximately 0.3 part per million.

Because of the high morbidity and mortality rates associated with methyl mercury poisoning, especially in utero, pregnant women and nursing mothers should avoid consuming larger fish, because their mercury concentrations tend to be higher than those in smaller fish.

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Deterrence and Prevention

Workplace hygiene and careful monitoring and disposal of industrial waste are equally important in the prevention of mercury poisoning.

Because of the high morbidity and mortality rates associated with methyl mercury poisoning, especially in utero, pregnant women and nursing mothers should avoid consuming larger fish because their mercury concentrations tend to be higher than those in smaller fish.

Minamata disease can be prevented by reducing or eliminating one's consumption of fish caught from bodies of water that are contaminated with high concentrations of mercury.

Other forms of mercury exposure, such as elemental mercury vapor inhalation, occur when people vacuum or sweep mercury spills in an enclosed space. The proper authorities must handle any spill with the appropriate mercury decontamination kits and procedures.

Significant oral ingestion of elemental mercury may lead to significant environmental contamination as the mercury is passed, essentially unabsorbed, through the GI tract and expelled in the feces.

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Medication Summary

As previously discussed, 2,3-dimercaptosuccinic acid (DMSA) and N -acetyl-D,L-penicillamine have been used as chelating agents in the treatment of mercury toxicity. Use chelating agents if the patient is symptomatic, systemic absorption is anticipated, or increased blood or urine levels are present. Chelating agents should be administered early in treatment.

GI decontamination may be useful only in acute, recent ingestions. Activated charcoal is indicated for GI decontamination because it binds inorganic and organic mercury compounds to some extent.

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Succimer (Chemet)

• Dosing, Interactions, etc.

Clinical Context:  DMSA is used in inorganic and organic mercurials. It is considered superior to penicillamine because it has fewer adverse effects. Because of this agent's ease of use, good efficacy, and safety, initiate treatment with DMSA if good evidence indicates that significant absorption can occur (mercury levels may not be readily available). DMSA is the chelator of choice in cases of chronic or mild toxicity.

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Dimercaprol (BAL)

• Dosing, Interactions, etc.

Clinical Context:  This is the drug of choice for the treatment of acute inorganic mercury toxicity. It is the preferred chelator for mercury salts. Dimercaprol is administered intramuscularly every 4 hours, mixed in a peanut oil base. It is excreted in urine and bile. Dimercaprol may be given to patients with renal failure. The BAL-mercury complex is dialyzable. Dimercaprol is used only in acute ingestion.

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D-penicillamine (Depen, Cuprimine)

• Dosing, Interactions, etc.

Clinical Context:  D-penicillamine is an oral, thiol-based chelator for acute or chronic toxicity. It is less well tolerated than DMSA (succimer). D-penicillamine forms a complex with mercury and is excreted in urine; therefore, do not use it in renal failure. This agent cannot be considered a first-line drug, because DMSA is safer and more effective.

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Class Summary

These agents are used to help remove a portion of the body's mercury stores. They are administered early in treatment because mercury binds to the body's ubiquitous sulfhydryl groups. Chelating agents are thought to use their thiol groups to compete with sulfhydryl groups in binding methyl mercury. The effectiveness of chelation in preventing or treating neurologic toxicity has not been well evaluated.

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Activated charcoal (Actidose-Aqua, Charcoal Plus DS, EZ-Char)

• Dosing, Interactions, etc.

Clinical Context:  Activated charcoal has a network of pores that adsorbs 100-1000mg of drug per gram of charcoal. It does not dissolve in water.

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Polyethylene glycol (CoLyte, GoLYTELY, NuLYTELY, Trilyte)

• Dosing, Interactions, etc.

Clinical Context:  This is a laxative with strong electrolyte and osmotic effects that has cathartic actions in the GI tract.

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Class Summary

These agents are empirically used to minimize systemic absorption of the toxin. They may be of benefit only if they are administered within 1-2 hours of ingestion.

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