By Stephen Thornton, MD
Introduction
Mercury remains a common heavy metal exposure as it can be found in both the home and industrial setting. The toxicology of mercury (Hg) is complex due to the presences of different states (elemental, inorganic, and organic), different routes of exposure (inhalation vs. ingestion), and distinctly different pathological effects (acute vs. chronic). Further complicating the picture is that mercury has deleterious effects on many organic systems, ranging from the brain to the kidney to the skin. The evaluation of mercury exposure and toxicity is equally confusing as the limitations of laboratory testing must be appreciated. The treatment of mercury toxicity relies on cessation of the exposure and good supportive care. Chelation can be considered but its indications and benefits are not clear.
Case presentation
An emergency physician calls the Poison Control Center because a patient has been referred to the emergency department for the complaint of “mercury poisoning” and has a laboratory print out detailing a whole blood mercury level of 1208 mcg/L (normal 0-10 mcg/L). The patient states she was exposed to mercury via a broken thermostat. The patient complains of rash to her face and arms, generalized fatigue, and a dry cough for several weeks. Her laboratory values in the emergency department are normal, including kidney function. A chest x-ray was done and read as normal. The treating physician is calling asking for recommendations for treatment and disposition of this patient.
Questions
- What are the different forms of mercury?
- What toxicity does each form of mercury cause and by what route of exposure?
- What role does laboratory evaluation play in mercury toxicity?
- How is mercury toxicity treated?
Epidemiology
Mercury is a naturally occurring element. It is present in three distinct forms in the environment: elemental, inorganic, and organic.
Elemental or metallic mercury is unique among all metals in that it is a liquid (“quicksilver”) at room temperature. Exposures to elemental mercury are typically via inhalation and are most common in the occupational setting but children are frequently exposed via broken thermometers and thermostats. Exposure to the amount of elemental mercury typically found in a broken thermometer is not usually medically significant. Rarer, but potentially more deadly, are exposures that result from home metallurgy use of metallic mercury. Frequently this involves heating the metallic mercury which dramatically increases the mercury vapor content in the air and is well reported to cause fatalities. A similar but less deadly increase in volatilization of elemental mercury can occur if attempts are made to use a vacuum to clean up spills on floors or carpets.
Inorganic mercury is typically encountered as mercuric oxide, mercuric sulfide (cinnabar), mercurous chloride (calomel), or mercuric chloride (corrosive sublimate). In the past, these notorious inorganic mercury compounds were used as treatment for many ailments such as syphilis and even as teething medications. Ingestion is the most common source of exposure and is typically intentional though they also can occur through herbal preparations and traditional medicines.
Organic mercury exists as short chain alkyl-mercury compounds and long chain aryl-mercury compounds. Methylmercury, a short chain compound, is the most commonly encountered organic mercury and exposure is primarily through seafood consumption. Other sources of organic mercury exposures include contaminated grain seeds (where the organic mercury compound can be used as a fungicide) and in the laboratory setting.
Pathophysiology and clinical effects
While the pathophysiology of mercury is dependent on the form of mercury and the route of exposure, there are several unifying themes: mercury most likely exerts its toxicity via binding and inactivation of sulfhydryl containing proteins resulting in widespread cellular dysfunction, and it typically affects multiple organ systems including the lung, brain, GI tract, and kidney.
Elemental mercury results in significant toxicity when inhaled. Elemental mercury has a vapor pressure of 0.002 mm Hg at 25°C and will slowly evaporate at room temperatures. This can be markedly increased by heating or agitation of elemental mercury and can result in mercury vapor levels in excess of 15 mg/m3 (levels > 10 mg/m3 are considered immediately dangerous to life or health). Elemental mercury is well absorbed by the lungs and results in malaise, cough, and shortness of breath within hours of exposure. GI complaints of nausea and vomiting may be present. The pulmonary effects can rapidly progress to pneumonitis, acute lung injury, and death. Survivors will often have residual chronic lung disease. Of note, mercury vapor is heavier than air which increases the risk of exposure to pediatric patients. Intentional subcutaneous or intravenous injection of elemental mercury results in toxicity similar to chronic inorganic mercury exposure, but can also result in severe tissue damage that may require extensive surgical debridement. On the contrary, ingestion of elemental mercury is generally benign and as there is almost no absorption of this form from the GI tract. Aspiration is more of concern than the actual ingestion.
Ingestion is the typical route of exposure with inorganic mercury and acutely results in significant gastrointestinal irritation and hemorrhage that can be life threatening. Subsequent absorption of mercuric ions (Hg2+) from the GI tract results in renal injury or failure (acute tubular necrosis) and, to a lesser degree, CNS toxicity. Chronic toxicity from low level inorganic mercury exposure either through ingestion or transdermally can manifest in several ways. Typically the CNS, GI, and renal systems are affected. CNS symptoms include an intention tremor, neurasthenia, and erethism. Neurasthenia is a nonspecific constellation of fatigue, malaise, headache, hypersensitivity to stimuli, and psychosomatic complaints. Erethism classically describes the extreme shyness and pronounced blushing of chronic inorganic mercury poisoned individuals. GI effects seen include gingivostomatitis, hypersalivation (ptyalism), non-specific abdominal pain, and nausea. A metallic taste is sometimes reported. Significant renal dysfunction can occur with chronic inorganic mercury exposure, sometimes leading to nephrotic syndrome or chronic renal failure. Acrodynia which is an idiosyncratic, immune mediated response to mercury ions is characterized by a pink, papular rash along with skins changes to the palms, soles, and face. CNS symptoms (anxiety, tremor, irritability) accompany the rash.
Exposure to organic mercury (ex. methylmercury, ethylmercury) is almost always via ingestion, typically of seafood. The toxicity of organic mercury is unique in that there is rarely an acute phase. Rather, there is a latent period of weeks or months after the ingestion which is then followed by the development of neurological toxicity that can often be permanent. Tremor, headache, ataxia, dysarthria, developmental decline, and even death have all been reported with methylmercury exposures. Children and the developing fetus are especially sensitive to the neurotoxic effects of organic mercury as was witnessed in the Minamata Bay disaster in Japan where the ingestion of methylmercury contaminated seafood resulted in severe fetal neurotoxicity. Of special note, dimethylmercury has been described to cause progressive neurological decline and death after what was thought to be only a minor dermal exposure and extreme caution is warranted when dealing with possible dimethylmercury exposures.
Diagnostics
The laboratory evaluation of the potentially mercury poisoned patient is ancillary and best serves to confirm exposure and response to treatment. Mercury can be measured in both whole blood and urine. Whole blood mercury is a useful marker of acute exposure. However, as mercury redistributes into tissues the blood level will decline even as organ toxicity manifests. Normal whole blood mercury levels are reported to be less than 10 mcg/L. Urinary mercury levels can also confirm acute exposure but are more useful than whole blood in evaluating chronic exposure. Both spot and twenty-four hour urine collection samples are used. Urine mercury concentrations less than 20 mcg/L are considered normal. It is important to note that organic mercury is eliminated via feces and not urine, so urine testing plays little role in the workup of patients that may be toxic from organic mercury. In addition, “normal” blood and urine mercury levels need to be interpreted with caution. No consistent correlation has been established between levels and toxicity. Some patients can have markedly elevated levels with minimal symptoms while others will manifest toxicity with only mildly elevated concentrations. Furthermore, spuriously elevated levels from recent seafood ingestion or herbal preparations can make interpretation of blood levels difficult. It is possible to differentiate organic and inorganic mercury but is not routinely done. Rather, when faced with an unexpectedly elevated blood mercury level in the asymptomatic patient, it is reasonable to instruct the patient to avoid all seafood and herbal preparations that may contain “natural” sources of organic mercury and undergo retesting in two weeks or more.
When evaluating a potentially mercury toxic patient, several other diagnostic tests are important to consider in addition to blood or urine mercury concentrations. As the kidneys are frequently affected by mercury, serum creatinine should be assessed. Evaluation for proteinuria should also be preformed since this is a common manifestation of mercury-induced renal disease. A chest radiograph should be considered when inhalation of elemental mercury is suspected. In certain mercury salt ingestions where corrosive effects are common, endoscopy may be considered to evaluate the extent of caustic injury.
Treatment
The first and most important step in the treatment of a mercury toxic patient is removal from the source of mercury exposure, whether it is elemental, inorganic, or organic mercury. Addressing and stabilizing the patient’s airway, breathing, and circulatory status should be the next priority. In significant elemental mercury inhalations respiratory status can decline precipitously, sometimes requiring intubation and ventilator support. Inorganic mercury ingestions can cause significant GI hemorrhage and fluid loss requiring aggressive fluid resuscitation.
Decontamination plays a limited role in the management of the mercury poisoned patient and cannot be routinely recommended unless an inorganic salt form has been recently ingested prompting consideration of gastric lavage or whole bowel irrigation. Removal of mercury from the body can be accelerated by various chelation agents, but the exact indication and benefit in treating mercury toxicity remains poorly defined. The principle behind the use of chelation agents is that they contain multiple sulfhydryl groups that bind free mercury and promote urinary elimination of the complex. Most toxicologists recommend chelation therapy for mercury toxicity based on an appropriate history of significant exposure and concerning clinical symptoms. Blood and urine levels can be used to guide the duration of therapy but there is no evidence for threshold levels which by themselves trigger either initiation of chelation therapy or its end point. The choice of chelation agent is largely dependent on the patient’s clinical condition. If the patient is unable to take oral medications, then BAL (dimercaprol) can be given via deep intramuscular injections at a dose of 5 mg/kg every 4 hours for 48 hours, followed by a gradual titration consisting of 2.5 mg/kg every 6 hours for 48 hours, and then 2.5 mg/kg every 12 hours for 7 days. Due to animal evidence of potential harm, BAL should not be used in cases of suspected organic mercury toxicity. It should be noted that organic mercury toxicity responds poorly to chelation in general. Also, an allergy to peanuts is a contraindication to BAL use as it is formulated in peanut oil. If the patient can tolerate oral medications, then succimer (DMSA) can be used in place of BAL. Succimer is dosed at 10 mg/kg orally three times a day for 5 days, and then 10 mg/kg orally twice a day for 14 more days. There are no specific contraindications to succimer, but as with all chelators, necessary trace elements such as copper and zinc should be monitored as chelation can deplete these metals as well. It is important to remember that since chelated mercury is eliminated primarily by the kidneys, hemodialysis may be needed to assist in complex removal in the setting of acute renal failure.
Disposition
Asymptomatic patients or those with mild symptoms do not require admission to a hospital and can be managed at home either by simply removing the source of mercury exposure or with succimer chelation. Close follow-up is recommended to make sure mercury levels are trending downward, to watch for any adverse effects from the succimer, and to monitor for any permanent sequalae from the exposure.
Discussion of case questions
- What are the different forms of mercury?
Mercury exists in three forms: elemental, inorganic, and organic. - What toxicity does each form of mercury cause and by what route of exposure?
Elemental mercury typically causes pulmonary toxicity with some renal toxicity after inhalation. Inorganic mercury cause GI hemorrhage, renal toxicity, and CNS effects after ingestion. Organic mercury causes almost pure neurological toxicity after ingestion. - What role does laboratory evaluation play in mercury toxicity?
Whole blood and urine mercury levels can be used to confirm exposure and follow chelation therapy but levels are not diagnostic and there is no correlation with levels and toxicity. Basic laboratory tests may reveal evidence of renal toxicity from mercury but are otherwise of limited value. - How is mercury toxicity treated?
Stopping the exposure to mercury is of primary importance. Aggressive supportive care may be needed when dealing with pulmonary effects of elemental mercury toxicity and the GI hemorrhage of inorganic mercury ingestions. Finally, chelation therapy can be considered with the appropriate history and clinical symptoms. BAL can be used if the patient cannot tolerate oral medication but should be avoided in organic mercury toxicity and peanut allergy. Otherwise, can be given orally. In the setting of renal failure, hemodialysis may be needed.
