Heavy Metal Toxicity

Background

Some debate exists as to exactly what constitutes a "heavy metal" and which elements should properly be classified as such. Some authors have based the definition on atomic weight; others, on a specific gravity of greater than 4.0, or greater than 5.0. The actinides (the chemical elements with atomic numbers from 89 to 103, actinium through lawrencium; eg, uranium) may or may not be included. Most recently, the term "heavy metal" has been used as a general term for those metals and semimetals with potential human or environmental toxicity.^{[1, 2]} This definition includes a broad section of the periodic table under the rubric of interest.

Regardless of how one chooses to define the category, heavy metal toxicity is an uncommon diagnosis. With the possible exceptions of acute iron toxicity from intentional or unintentional ingestion and suspected lead toxicity, emergency physicians will rarely be alerted to the possibility of metal exposure. Yet, if unrecognized or inappropriately treated, heavy metal exposure can result in significant morbidity and mortality.

Many of the elements that can be considered heavy metals have no known benefit for human physiology. Lead, mercury, and cadmium are prime examples of such "toxic metals."

Yet, other metals are essential to human biochemical processes. For example, zinc is an important cofactor for several enzymatic reactions in the human body, vitamin B-12 has a cobalt atom at its core, and hemoglobin contains iron. Likewise, copper, manganese, selenium, chromium, and molybdenum are all trace elements that are important in the human diet. Another subset of metals includes those used therapeutically in medicine; aluminum, bismuth, gold, gallium, lithium, and silver are all part of the medical armamentarium. Any of these elements may have pernicious effects if taken in quantity or if the usual mechanisms of elimination are impaired.

The toxicity of heavy metals depends on a number of factors. Specific clinical manifestations vary according to the metal in question, the total dose absorbed, and whether the exposure was acute or chronic. The age of the person can also influence toxicity. For example, young children are more susceptible to the effects of lead exposure because they absorb several times the percent ingested compared with adults and because their brains are more plastic and even brief exposures may influence developmental processes. The route of exposure is also important. Elemental mercury is relatively inert in the gastrointestinal tract and also poorly absorbed through intact skin, yet inhaled or injected elemental mercury may have disastrous effects.^[3]

Some elements may have very different toxic profiles depending on their chemical form. For example, barium sulfate is basically nontoxic, whereas other more water-soluble barium salts are rapidly absorbed and cause profound, potentially fatal hypokalemia. The toxicity of radioactive metals like polonium, which was discovered by Marie Curie but only recently brought to public attention after the 2006 murder of Russian dissident Alexander Litvinenko, relates more to their ability to emit particles than to their ability to bind cell proteins.

Exposure to metals may occur through the diet, from medications, from the environment, or in the course of work or play. Where heavy metal toxicity is suspected, time taken to perform a thorough dietary, occupational, and recreational history is time well spent, since identification and removal of the source of exposure is frequently the only therapy required.

A full dietary and lifestyle history may reveal hidden sources of metal exposure. Metals may be contaminants in dietary supplements, or they may leach into food and drink stores in metal containers such as lead decanters. Persons intentionally taking colloidal metals for their purported health benefits may ultimately develop toxicity. Metal toxicity may complicate some forms of drug abuse. Beer drinker’s cardiomyopathy was diagnosed in alcoholics in Quebec, and later Minnesota, during a brief period in the 1970s when cobalt was added to beer on tap to stabilize the head. More recently, a parkinsonian syndrome among Latvian injection drug users of methcathinone was linked to manganese toxicity.

Classic examples of environmental contamination include the Minimata Bay disaster and the current epidemic of arsenic poisoning in South East Asia. In the 1950s, industrial effluent was consistently dumped into Japan’s Minimata Bay, and methylmercury bioaccumulated to exceedingly high concentrations in local fish. Although some adults did develop signs and symptoms of toxicity, the greatest impact was on the next generation, into which many were born with severe neurologic deficits.

Currently, millions of people living in and around Bangladesh are at risk for organ dysfunction and cancer from chronic arsenic poisoning from the water supply. In an effort to bypass ground water sources rife with bacterial contamination, tube wells were sunk throughout that area, deep into the water table.^[4]  Unfortunately, the bedrock in that part of the world is rich in arsenic, giving these deeper water stores—and the crops they irrigate—a high concentration of arsenic, and toxicity is epidemic throughout the area. Childhood lead poisoning linked to the ingestion of old paint chips in North America is another good example of environmental contamination.

Metals have been used with malicious intent as poisons. Arsenic is perhaps more rightly classified as a metalloid, but it is consistently the single substance most commonly thought of as a poison. Metals have also been used in warfare as chemical weapons. Again, arsenic was the primary component of the spray known as Lewisite that was used by the British during trench warfare in World War I. Exposure produced severe edema of the eyelids, gastrointestinal irritation, and both central and peripheral neuropathies.

The first antidote to heavy metal poisoning, and the basis for chelation therapy today, was British Anti-Lewisite (BAL, or dimercaprol), a large molecule with sulfhydryl groups that bind arsenic, as well as other metals, to form stable covalent bonds that can then be excreted by the body. BAL was developed by the British during World War II in anticipation of a reinitiation of chemical warfare as had been waged earlier in the century.

In total, however, occupational exposure has probably accounted for the vast majority of heavy metal poisonings throughout human history. Hippocrates described abdominal colic in a man who extracted metals, and the pernicious effects of arsenic and mercury among smelters were known even to Theophrastus of Erebus (370-287 BC).

The classic acute occupational heavy metal toxicity is metal fume fever (MFF), a self-limiting inhalation syndrome seen in workers exposed to metal oxide fumes. MFF, or "brass founder’s ague," "zinc shakes," or "Monday morning fever" as it is variously known, is characterized by fever, headache, fatigue, dyspnea, cough, and a metallic taste occurring within 3-10 hours after exposure. The usual culprit is zinc oxide, but MFF may occur with magnesium, cobalt, and copper oxide fumes as well.

Chronic occupational exposure to metal dusts has also been linked to the development of pneumoconioses, neuropathies, hepatorenal degeneration and a variety of cancers. These syndromes develop slowly over time and may be difficult to recognize clinically. In the United States, Occupational Safety and Health Administration (OSHA) regulations guide the surveillance of workers at risk and suggest exposure limits for metals of industrial importance.

This article provides a brief overview of general principles in the diagnosis and management of metal toxicity. The Table below reviews the typical presentation of the most commonly encountered metals and their treatment in summary form. It is not intended to guide clinical decision-making in specific cases.^{[5, 6, 7, 8, 9]}

Table. Typical Presentation of the Most Commonly Encountered Metals and Their Treatment

View Table

See Table

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Pathophysiology

The pathophysiology of the heavy metal toxidromes remains relatively constant. For the most part, heavy metals bind to oxygen, nitrogen, and sulfhydryl groups in proteins, resulting in alterations of enzymatic activity. This affinity of metal species for sulfhydryl groups serves a protective role in heavy metal homeostasis as well.

Increased synthesis of metal binding proteins in response to elevated levels of a number of metals is the body's primary defense against poisoning. For example, the metalloproteins are induced by many metals. These molecules are rich in thiol ligands, which allow high-affinity binding with cadmium, copper, silver, and zinc among other elements. Other proteins involved in both heavy metal transport and excretion through the formation of ligands are ferritin, transferrin, albumin, and hemoglobin.

Although ligand formation is the basis for much of the transport of heavy metals throughout the body, some metals may compete with ionized species such as calcium and zinc to move through membrane channels in the free ionic form. For example, lead follows calcium pathways in the body, hence its deposition in bone and gingivae. Thallium is taken up into cells like potassium because of their similar ionic radii.

Nearly all organ systems are involved in heavy metal toxicity; however, the most commonly involved organ systems include the CNS, PNS, GI, hematopoietic, renal, and cardiovascular (CV). To a lesser extent, lead toxicity involves the musculoskeletal and reproductive systems. The organ systems affected and the severity of the toxicity vary with the particular heavy metal involved, the chronicity and extent of the exposure, and the age of the individual.

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Epidemiology

Frequency

United States

Lead

Within the United States, lead remains the most frequently encountered toxic metal, owing to long-term exposure. In children, exposure has been shown to be a result of living in houses that contain lead paint. It is currently estimated that approximately 4 million households within the United States have children living within them that are being exposed to lead.^[10]

Evidence has shown that lead blood levels less than 10 μg/dL have been shown to have adverse neurodevelopmental outcomes in children younger than 5 years.^[11] The US Centers for Disease Control and Prevention (CDC) Advisory Committee on Childhood Lead Poisoning Prevention estimates that approximately 74,110 children aged < 5 years had a blood lead level of 5–9 µg/dL in 2013 (5 μg/dL is the level at which the CDC recommends that public health actions be initiated). In the US in 2013, 8,230 new cases of blood lead levels ≥10 µg/dLwere reported in children aged < 5 years.^[10]

The median concentration of lead in the blood of children age 1 to 5 years dropped from 15 µg/dL in 1976–1980 to 0.7 µg/dL in 2013–2014, a 95% decrease. The largest declines in blood lead levels corresponded with the US Environmental Protection Agency phasing out leaded gasoline from 1973-1995.^[12]

Lead exposure in the adult population is more commonly occupational, namely in mining, manufacturing, and construction. Overall, the national prevalence rate of blood lead levels ≥10 μg/dL in employed adults declined from 26.6 per 100,000 in 2010 (among 37 states) to 20.4 in 2013 (among 29 reporting states). In 2013, of the 4,547 adults with blood lead levels ≥25 μg/dL who had a known lead exposure history, 93.7% had occupational exposure^[13]

In 2016, the National Poisoning Data System (NPDS) of the American Association of Poison Control Centers (AAPCC) reported 2412 single exposures to lead. Of those exposures, 1188 were in children younger than 6 years, and 671 were in patients older than 19 years.^[14]

Arsenic

Exposure to arsenic within the United States can occur through many routes. It has been used with both criminal and suicidal intent as an agent to poison individuals or groups.^[15] Medications used to treat disease, such as the chemotherapeutic agent arsenic trioxide, are iatrogenic sources. Industrial exposure to the waste products of smelting plants is another potential source. Arsenic-containing pesticides are still used in some areas of the country, with its use mostly found in cotton fields.^[16]

According to the AAPCC, in 2016, there were 794 single exposures related to arsenic (excluding pesticides) and 20 exposures to arsenic-containing pesticides.^[14]

Iron

Iron toxicity in the United states is largely the result of ingestion of iron tablets or multivitamins but can also be a result of blood transfusions. Iron ingestion is particularly hazardous for children who unintentionally ingest iron-containing tablets.^[17] In adults, ingestion is largely intentional.

In 2016, the AAPCC reported 4295 single exposures to iron and iron salts (not including iron-supplemented multivitamins). Of those, 2204 were in children younger than 6 years and 1332 were in adults older than 19 years. There were 11,180 reported single exposures to multivitamins that contained iron. Of these exposures, 9086 were in children younger than 6 years.^[14]

Mercury

Mercury toxicity can occur through exposure to mercury in its pure elemental form, as an inorganic salt, or through organic mercury compounds. Toxicity to the pure elemental form stems largely from inhalation of mercury vapor as a result of occupational exposure, for example melting mercury-containing dental amalgam. Another common route is vacuuming spilled mercury from a broken thermometer. Exposure to the inorganic salts and organic compounds stems largely from ingestion.^[18]

Industrial emissions of mercury have polluted fresh and coastal waters, leading to contamination of fish. This has raised public concerns about long-term exposure to mercury through the consumption of wild fish.^[19]

In 2016 the AAPCC reported 1126 single exposures to elemental mercury (excluding thermometers). Of these exposures, 90 were in children aged 5 years or younger and 553 were in adults aged 20 years or older. There were 1080 exposures to mercury-containing thermometers, 224 of them in children aged 5 years or younger and 351 in adults aged 20 years and older.^[14]

International

Heavy metal toxicity has emerged as a significant occupational hazard associated with electronics recycling in China and South East Asia. Much of the recycling industry there takes place within the informal sector, and the use of personal protective equipment (eg, respirators) is poorly regulated and uncommon.

Large-scale epidemics of lead poisoning were reported in China in 2009, involving more than 2000 children living near smelting plants and sparking riots.^{[20, 21]} The true prevalence of lead poisoning in childhood worldwide is not well understood. Availability of leaded gasoline, paint, cosmetics, and piping in many lower income countries suggests that there is a significant if under-recognized burden of toxicity.

Studies of street dust in Chinese cities have found elevated levels of heavy metals in street dust. These have included cadmium, chromium, and arsenic posing potential risk of carcinogenicity.^[22]

Chronic arsenic toxicity is epidemic in Bangladesh and contiguous areas of the Indian subcontinent, where arsenic is an important component of bedrock. Deep tube wells constructed to provide an alternative water source to bacteriologically suspect surface deposits frequently supply water with a high arsenic content, with major public health consequences for the region.

Mortality/Morbidity

As previously noted, heavy metal toxicities are relatively uncommon. However, failure to recognize and treat heavy metal toxicities can result in significant morbidity and mortality.

Studies of a possible association of toxic metals and autism have yielded inconsistent results. Adams et al reported significantly higher average excretion levels of lead, tin, thallium, and antimony in 67 patients with autism spectrum disorder, compared with 50 neurotypical controls.^[23]

Encephalopathy is a leading cause of mortality in patients with both acute and chronic heavy metal toxicity.

Race- and Sex-related Demographics

In the United States, a higher incidence of lead toxicity occurs in the African-American population because of delays in removing lead sources from the environment in lower socioeconomic areas.

Little or no difference in prevalence exists between the sexes. Occupations with heavy metal exposure that predominantly involve a particular sex are associated with higher rates of exposure in that sex.

Age

Several points are of concern in heavy metal toxicity with respect to age. Generally, children are more susceptible to the toxic effects of the heavy metals and are more prone to unintentional exposures.

Inorganic lead salts enter the body by way of ingestion or inhalation. For adults, only about 10% of the ingested dose is absorbed. In contrast, children may absorb as much as 50% of an ingested dose.

The percentage of absorbed lead is increased with deficiencies of iron, calcium, and zinc. It is also increased with a predominantly milk diet, possible due to the high lipid content.

Children and infants are prone to developmental delays secondary to lead toxicity. One study found that blood lead concentrations obtained in children aged 6 years is more strongly associated with cognitive and behavior development than blood lead concentrations measured in 2-year-olds.^[24]

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History

A history of exposure is the most critical aspect of diagnosing heavy metal toxicity. A complete history includes questions about potential occupational exposures, hobbies, recreational activities, and potential environmental exposure.

A complete dietary history should be taken, especially the ingestion of fish, seafood, and seaweed products since these will frequently be implicated as dietary sources of organic (and relatively nontoxic) mercury, arsenic, or both. The timing of ingestion relative to the collection of urine samples is critical to interpreting the results.

Herbal medications and dietary supplements are also potential sources of heavy metal exposure. Many Ayurvedic and Chinese patent medicines contain heavy metals.

Most acute presentations of heavy metal toxicity involve industrial exposure.

The ingestion of nonfood items such as paint chips, toys, and ballistic devices has also been implicated as the source of metal exposure in several cases.

Retained lead shot may ultimately lead to toxicity as well, although generally the shot must be bathed in relatively acidic body compartments such as the peritoneal fluid, pleural fluid, cerebrospinal fluid, or  synovial fluid for significant absorption of metal ions to occur.

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Physical

The physical examination of patients with suspected metal toxicity should focus on the most commonly involved organ systems: the nervous, gastrointestinal, hematologic,^[25] renal, and integumentary systems. See the Table in Overview for common presentations of acute and chronic exposures to specific metals.

Nausea, persistent vomiting, diarrhea, and abdominal pain are the hallmark of most acute metal ingestions. Dehydration is common. Metal salts are generally corrosive.

Encephalopathy, cardiomyopathy, dysrhythmias, acute tubular necrosis, and metabolic acidosis are also commonly seen with acute, high-dose exposures to most metals.

Patients with chronic metal toxicity tend to have more prominent involvement of the central and peripheral nervous systems. However, encephalopathy and peripheral neuropathies may occur within a few hours to days of acute high-dose exposure.

A classic presentation of chronic metal exposure includes anemia, Mees lines (horizontal hypopigmented lines across all nails), and subtle neurologic findings. These findings should prompt suspicion of heavy metal toxicity in any patient regardless of chief complaint.

Because lead toxicity is relatively common, any combination of GI complaints, neurologic dysfunction, and anemia should prompt a search for lead toxicity.

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Laboratory Studies

Specific laboratory testing for metals should be undertaken when the likelihood of toxicity is significant, based on a history and/or symptoms consistent with excessive exposure. See the relevant articles for more detailed recommendations regarding the most reliable testing measures for individual metal toxicity, as follows:

• Lead Toxicity
• Mercury Toxicity
• Arsenic Toxicity
• Iron Toxicity

When specific testing is indicated, samples should be sent in metal free containers.

Hair analysis is not generally reliable and rarely indicated.

Patients should be instructed to abstain from seafood and seaweed products prior to testing for metals such as arsenic and mercury, since elevated concentrations in patients who have not done so for at least several days to 1-2 weeks may simply reflect nontoxic organic forms ingested in the diet. Samples with elevated concentrations may also be sent for speciation for either of these metals to determine the relative contributions of organic forms versus inorganic forms.

The following standard laboratory determinations may help make the diagnosis of heavy metal toxicity or help gauge its severity:

• Complete blood cell count (CBC) with peripheral smear - Findings may include basophilic stippling of the RBCs on peripheral blood smears; basophilic stippling is not specific for lead toxicity and may be observed in arsenic toxicity, sideroblastic anemia, and thalassemia; the anemia of lead toxicity may be normocytic or microcytic.
• Renal function tests
• Urine analysis (look for proteinuria)
• Liver function studies

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Imaging Studies

Abdominal radiographs are indicated in acute ingestions. Radio-opacities demonstrable in the gastrointestinal tract should be cleared by whole-bowel irrigation prior to instituting chelation therapy. Large, retained gastric foreign bodies (eg, bullets, shotgun cartridges, fishing sinkers, curtain weights) may cause lead toxicity and should be removed endoscopically if they do not pass, if serum lead concentrations are concerning or increasing, or if the patient becomes symptomatic.

Several reported cases of patients who have injected elemental mercury subcutaneously and developed mercury toxicity have been documented. Radiographs of the suspect areas showing large subcutaneous deposits of radio-opaque material were helpful in confirming the diagnosis and need for surgical intervention to limit the exposure.

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Other Tests

Electrocardiographic abnormalities may provide diagnostic clues in metal toxicity.

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Emergency Department Care

Decontamination

Removal of the patient from the source of exposure is critical to limiting dose.

Treatment may include whole-bowel irrigation with polyethylene glycol electrolyte solution if radiographic studies show evidence of retained metal (toys, coins, paint chips) in the gastrointestinal tract.

Resuscitation

Good supportive care is critical. Ensure airway patency and protection, provide mechanical ventilation where necessary, correct dysrhythmias, replace fluid and electrolytes (significant fluid losses generally occur and require aggressive rehydration), and monitor and treat the sequelae of organ dysfunction.

Chelation

Chelation is rarely indicated in the emergent setting. A possible exception is lead encephalopathy. Consideration of chelation therapy for patients with suspected or confirmed metal exposures should be made in conjunction with a medical toxicologist or the local poison control center.

Guidelines

Clinical guidelines on treatment of iron and mercury exposure are available from the American Association of Poison Control Centers.^{[26, 27]}

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Consultations

Recommended consultations include the following:

• Contact a certified poison control center or medical toxicologist
• Consult a gastroenterologist if the possibility of corrosive GI effects is present
• If intentional ingestion or overdose is suspected, place the patient in a closely monitored unit, screen for coingestion of acetaminophen, and consult a medical toxicologist and psychiatrist

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Medication Summary

The most important therapeutic maneuver in many cases of metal toxicity is to remove the source of exposure.

Chelation regimens have been shown to enhance elimination of some metals, and thereby decrease the total body burden. See the Table for a list of accepted chelation agents for specific metals.

There is evidence of no benefit with chelation therapy for several metals, and evidence of increased toxicity after chelation of several others (eg, selenium). Therefore, routine chelation of patients with heavy metal exposure cannot be recommended, and the decision to chelate should be made in conjunction with a medical toxicologist or local poison control center.

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Dimercaprol (British Anti-Lewisite; BAL)

• Dosing, Interactions, etc.

Clinical Context:  DOC in the treatment of lead, arsenic, and mercury toxicity. Administered via deep IM injection only, q4h, mixed in a peanut oil base. Chelates intracellular and extracellular lead and is excreted in urine and bile. First choice for patients with lead encephalopathy, in conjunction with EDTA. May be given to patients with renal failure.

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Edetate calcium disodium (Calcium Disodium Versenate)

• Dosing, Interactions, etc.

Clinical Context:  Second-line for lead toxicity. Most effective when given early in the course of acute poisoning. Chelates only extracellular lead and may induce CNS toxicity if BAL therapy not initiated first. Begin therapy 4 h after BAL is given. Only given IV, and continuous infusion is recommended.

Not recommended with renal failure. Because of potential for renal toxicity, patient should be well hydrated. To prevent hypocalcemia, use only calcium disodium salt of EDTA for chelation in heavy metal toxicity.

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Penicillamine (Cuprimine, Depen)

• Dosing, Interactions, etc.

Clinical Context:  Metal chelator used in treatment of arsenic poisoning. Forms soluble complexes with metals that are subsequently excreted in urine.

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Succimer (Chemet)

• Dosing, Interactions, etc.

Clinical Context:  Contains 2 sulfhydryl groups capable of complexing to lead, making it water soluble

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Class Summary

These drugs supply sulfhydryl groups for the heavy metals to attach and, subsequently, may be eliminated from the body.

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Further Outpatient Care

The first priority in managing any patient with detectable serum lead is to determine the source of exposure and to remove the person from it. The finding of any elevated serum or urine metal concentration in an asymptomatic person should prompt a thorough dietary, occupational, and recreational history, and radiographs where indicated to identify any source of ongoing exposure. Occupational or recreational histories in parents can also reveal a source of exposure for children.

A majority of asymptomatic children and adults with elevated lead levels can be safely managed solely by removing the source of exposure. Contact a medical toxicologist or the local poison control center for specific recommendations.

All cases of significantly elevated lead levels should be reported to the local health department. Report any industry- or workplace-related heavy metal toxicities to OSHA.

Symptomatic patients with elevated metal concentrations should be treated more aggressively. Please refer to the relevant articles (see Arsenic Toxicity; Lead Toxicity; Mercury Toxicity; Iron Toxicity) or contact a medical toxicologist for more specific recommendations.

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Further Inpatient Care

Arsenic is frequently used for homicidal or suicidal purposes. Thoroughly scrutinize all arsenic toxicity cases for evidence of such activity. Report all cases with possible homicidal association to the proper legal authorities before discharge. Patients with suspected suicidal intent should undergo psychiatric evaluation before discharge from hospital.

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Complications

See the list below:

• Metal toxicity is rarely encountered clinically and may be challenging to recognize.
• If untreated, acute exposures may progress to multiorgan failure and death or permanent organ damage.
• Chronic exposure to metals may present with nonspecific symptoms, but if it is not identified and the exposure is allowed to continue, permanent neurologic damage, organ failure, or cancer may develop.

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