Characteristics and treatment of elemental mercury intoxication: A case series

Abstract Background and aims Elemental mercury toxicity is a rare condition which can be difficult to diagnose due to its nonspecific signs and symptoms. The purpose of this investigation is to describe the presenting characteristics and treatment of adult and pediatric patients with elemental mercury poisoning. Methods A retrospective review was performed in six patients with elemental mercury exposure or intoxication who were treated in an outpatient medical toxicology clinic. Clinical signs and symptoms, laboratory assessments, and public health responses were reviewed. Results Headache, anorexia, rash, and personality changes were commonly reported symptoms in pediatric patients; the adult patients were asymptomatic or reported signs and symptoms included myalgias, tremors, and hypertension. Delays in diagnosis were common. Symptomatic patients had 24‐hour urine mercury concentrations greater than 20 mcg/L. Treatment, including removal from the exposure source as well as chelation with dimercaptosuccinic acid, resulted in resolution of signs and symptoms within 6 months of diagnosis. Conclusion The evaluation and treatment of patients with suspected elemental mercury poisoning frequently require a multidisciplinary approach including medical toxicologists and public health officials. A heightened awareness of the clinical presentations of this condition, as well as early identification and removal of patients from the source of exposure and consideration of chelation therapy, can result in accelerated patient recovery.

as occupational endeavors such as gold mining and extraction. 3,4 The clinical presentation of elemental mercury intoxication is often nonspecific in nature and may be easily misdiagnosed. The signs and symptoms of elemental mercury intoxication are distinctly different from the clinical effects of other forms of mercury intoxication; inorganic mercury toxicity results in gastrointestinal and neurological symptoms, while organic dimethylmercury exposure is associated with delayed cerebellar damage which is often fatal. 5,6 As elemental mercury intoxication is rarely encountered in clinical practice, physicians caring for patients with suspected mercury toxicity may be unaware of the clinical characteristics of this disease process as well as the diagnostic methods and available treatments for this condition.  The first case involved an exposure that affected a family of five individuals. In this case, a previously healthy 4-year-old boy developed a constellation of unexplained signs and symptoms, including diaphoresis, headache, tactile sensitivity, unwillingness to ambulate, decreased appetite, insomnia, and nonischemic priapism. Symptoms occurred approximately 1 month after the patient's family moved into a new home. The patient's two sisters (ages 6 and 8 years) developed personality changes and complained of headaches. The family dog also became ill and died unexpectedly. Due to their severe symptoms, the 4-year-old boy and his oldest sister were unable to attend school on a full-time schedule. On physical examination, the boy was irritable and withdrawn; he would not ambulate and was transported in a stroller by his parents. After a comprehensive medical workup was unrevealing, the family's pediatrician ordered a 24-hour urine assay for heavy metals for the youngest child, which revealed an elevated urine mercury concentration ( Table 1). The patient's siblings and parents were then tested and were found to have elevated urine mercury concentrations. The local fire department evaluated the patient's home and detected the presence of elevated mercury vapor concentrations within the residence. The family was evacuated from the home for several weeks, while residential mercury assessment and remediation were conducted. The children were evaluated in an outpatient medical toxicology clinic and were prescribed oral chelation therapy with dimercaptosuccinic acid (DMSA [10 mg/kg every 8 hours for 5 days, followed by 10 mg/kg every 12 hours for 14 days]); their parents, who were asymptomatic and had normal physical examinations, were not offered chelation therapy. The source of the exposure was eventually traced back to a spill of elemental mercury in the home which occurred prior to the patient and his family moving into the residence. The highest concentrations of mercury vapor were identified in the home's basement, adjacent to the heating, ventilation, and air conditioning (HVAC) system. Mercury from the spill had likely entered the HVAC system and traveled through the ductwork to the other residential areas, leading to inhalational mercury vapor exposure for the entire family. The previous homeowner did not provide additional details on the prior use of mercury in the home, and it is unknown if this individual had symptoms related to mercury vapor exposure. Once remediation was completed, the family moved back into the home. The children's symptoms improved over the following several months. Over 3 years later, all family members remained asymptomatic.
The second case involved an adult female who developed proximal muscle pain, dental pain, night sweats, tremors, and hypertension.
Her primary care physician referred her for neurological and rheumatological evaluations; her erythrocyte sedimentation rate was found to be elevated, and electromyography demonstrated borderline peripheral neuropathy. Other laboratory assays, including complete blood count and comprehensive metabolic panel, were unremarkable.
A urinalysis was positive only for moderate blood. She was diagnosed with fibromyalgia and treated with tramadol, trazodone, meloxicam, and physical therapy. Amlodipine and hydrochlorothiazide were prescribed for hypertension. The patient researched her symptoms online and became concerned that she was affected by heavy metal poisoning. She requested testing from her primary care physician; a 24-hour urine heavy metal screen revealed an elevated urine mercury level, and a whole blood mercury concentration was also elevated. The

| RESULTS
Patient demographic information and pertinent laboratory values are presented in Table 1. Serial urine mercury concentrations were obtained from all symptomatic patients, and serial blood mercury concentrations were obtained from the symptomatic adult patient.
Elimination half-lives were calculated by the nonlinear least-

| DISCUSSION
Elemental mercury is a dense, silvery-colored metal that exists in a liquid state at room temperature. It is 13 times denser than water; due to this, estimation of spill severity may be misleading as small volumes may correspond with large amounts of the compound. 7 A "small" mercury spill is often defined as the equal to or less than the amount of mercury in a fever thermometer (generally <0.7 g). 7 While small mercury spills are generally not associated with elevated mercury vapor concentrations, the vapor can easily accumulate in small, poorly ventilated, or low-lying areas, increasing the potential for toxicity. 7 For small spills, mercury removal from hard surfaces can be achieved Urine mercury concentration (mcg/L)

Months after exposure
Urine mercury concentration over time by using cardboard, masking tape, and eyedroppers; commercially available powdered sulfur may also be used to adsorb elemental mercury from hard surfaces. 7,8 Larger mercury spills require comprehensive evaluation and specialized remediation.
Inhalational exposure represents the primary source of toxicity after elemental mercury exposure. Ingestion does not result in significant exposure as elemental mercury is poorly absorbed from the gastrointestinal tract, and dermal penetration is also limited. 11,12 Approximately 80% of an inhaled dose of elemental mercury is absorbed by the lungs and systemically distributed throughout the circulation to all organs. Absorbed elemental mercury is oxidized in vivo to form inorganic mercurous (Hg + ) and mercuric (Hg +2 ) ions; these ions bind with sulfhydryl groups, leading to inactivation of enzymes and altered cell membrane permeability. 13 The proximal convoluted tubule is the primary site of deposition of inorganic mercury, and renal excretion predominates. 14 Elemental mercury vapor exposure can affect multiple organ systems, with the brain and kidneys primarily affected. 15 Elemental mercury crosses the blood-brain and placental barriers readily. 16 Children are more susceptible than adults to the toxic effects of mercury vapor, as their short stature places them in closer proximity to the ground where dense mercury vapors settle. 17 In addition, children have a higher minute ventilation than adults, leading to increased inhalation of mercury vapors. 18 The signs and symptoms of mercury vapor intoxication can be subtle and nonspecific in nature and may include weakness, pain, anorexia, weight loss, and gastrointestinal or neurologic symptoms. 14 After an acute high-level exposure to mercury vapor, pneumonitis characterized by fevers, cough, and dyspnea may occur with hours and may result in mortality due to progressive hypoxia. 19,20 In children, the most common presenting symptom of mercury poisoning is headache; this was a significant presenting symptom in each of the children in this case series. 20 Mercury interferes with catecholamine breakdown by inactivation of catecholamine-O-methyltransferase, leading to accumulation of catecholamines and development of hypertension, diaphoresis, and tachycardia in some patients. 21 Acrodynia or "pink disease," a syndrome characterized by painful pink discoloration and peeling of the hands and feet, is occasionally noted in young children exposed to elemental mercury; the etiology of acrodynia may be related to an underlying hypersensitivity to mercury. 22 Mercurial erethism, which was noted in several patients in this series, is characterized by personality changes including irritability, insomnia, and shyness. 23 Given the renal excretion pattern of elemental mercury, urine is the preferred method of diagnosis for most elemental mercury exposures. Urine is also the best marker of exposure for most inorganic mercury exposures; as organic mercury is excreted through the bile and feces, it is not readily detectable in the urine. 5 Elemental mercury exposures often represent public health dangers and may require involvement of local, regional, or national authorities for assessment and remediation. The geographical locations of mercury exposure in this case series involved three separate states. The public health response varied between jurisdictions; depending on the location, mercury vapor assessment was provided by the local health department, state Emergency Response team, or local fire department. While state and regional health departments are useful resources for the initial assessment of recreational or elemental mercury exposures, their availability, resources, and engagement can vary based on location. 30 In the United States, the Environmental Protection Agency (EPA) can respond to larger elemental mercury spills that represent an imminent and substantial endangerment to public health. 31 Elemental mercury spills of more than one pound or 453 g (the equivalent of two tablespoons or 30 mL) must be reported to the EPA's National Response Center (NRC) at phone number 800-424-8802. The NRC hotline is available 24 hours a day, 7 days a week. 32 After the source of mercury exposure is identified, remediation may be indicated. Remediation should be performed by experienced contractors. The remediation process may be lengthy; for residential exposures, temporary relocation of home dwellers may be required.
Identification and elimination of the source of mercury exposure is of paramount importance for the treatment of patients with elemental mercury toxicity. In addition, chelation therapy is often utilized for patients with mercury poisoning who are symptomatic; however, the clinical benefit of chelation therapy in symptomatic patients is poorly defined, and this treatment is of lesser significance than identification and removal of the exposure source. 33 Chelation agents form chemically inert and nontoxic complexes with metal ions, which are then excreted. 34 Since chelation therapy releases metals from body tissues, urine mercury concentrations may transiently increase upon initiation of chelation therapy before significant decreases occur. 21 Chelators used in the treatment of mercury intoxication may include States. These drug shortages, which often affect the supply of orphan drugs used to treat rare diseases, have increased in recent years and represent a significant public health concern in the United States. 35 In this case series, DMSA was able to be obtained from local chain pharmacies. The pharmacies did not carry it in their normal stock and had to order it as a "drop ship" from the manufacturer; this resulted in a 1-to 2-week delay in delivery to the patients. Once obtained, the patients in this series tolerated DMSA chelation without significant complications. Common adverse effects associated with DMSA administration include bad taste and smell, mild gastrointestinal complaints, elevation of hepatic transaminases, and increased excretion of trace elements such as zinc and copper. 36 Overall, DMSA is well tolerated by most individuals; for the youngest children in this series, palatability of DMSA was enhanced by opening the capsules and mixing the contents with chocolate frosting, applesauce, or pudding.
DMPS may also be considered as a chelating agent for mercury intoxication. DMPS, a water soluble analogue of BAL, is produced and marketed by the German pharmaceutical company Heyl, Berlin; it is approved in Germany for oral and intravenous treatment of acute heavy metal intoxications. 37 Although DMPS is not currently approved by the United States Food and Drug Administration for use in chelation therapy, it can be obtained through compounding pharmacies in oral or intravenous formulations. 38 DMPS has been successfully used in the treatment of mercury intoxication. 39 Compared with DMSA, DMPS remains in the body for longer, acts more quickly, and is more effective in chelating patients with inorganic mercury intoxication. 40 DMPS is generally well tolerated; it can cause a dosedependent increase in urinary copper excretion, and Stevens-Johnson syndrome has been reported to occur after administration of DMPS. 41,42 The patients described in this case series all had a favorable clinical outcome once the diagnosis of elemental mercury intoxication was established, suggesting that the significant clinical effects that may occur as a consequence of this intoxication are reversible with treatment including source identification and remediation as well as chelation therapy. A significant limitation of this analysis is the low number of patients included in this case series. As elemental mercury intoxication remains a rare diagnosis, most published descriptions of affected patients involve case reports or small case series.

| CONCLUSION
Although rarely encountered in medical practice, elemental mercury intoxication represents a public health concern that can be associated providers to have a heightened understanding of this condition, leading to decreased misdiagnosis due to implicit biases and increased awareness of the potential for mercury intoxication in patients who present with nonspecific signs and symptoms which cannot be attributed to another likely diagnosis.

CONFLICT OF INTEREST
The authors have no conflicts of interest to disclose. Kelly Johnson-Arbor affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.

INSTITUTION AND ETHICS APPROVAL AND INFORMED CONSENT
The work was performed at MedStar Georgetown University Hospital and was approved by the Georgetown University Institutional Review Board. Written informed consent for publication was also obtained from each patient described in the manuscript.

TRANSPARENCY STATEMENT
This manuscript is an honest, accurate, and transparent account of the study being reported. No important aspects of the study have been omitted; any discrepancies from the study as planned (and, if relevant, registered) have been explained.