Heavy Metal Toxicity

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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 point to those metals with a specific gravity of greater than 4.0, or greater than 5.0. The actinides 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 exposure, 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. This article provides a brief overview of general principles in the diagnosis and management of metal toxicity. The Table 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.

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, which 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 symptomatology varies 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.

Some elements may have very different toxic profiles depending on their chemical form. For example, barium sulfate is basically nontoxic, whereas 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 leech into food and drink stores in metal containers like 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 has been 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 mercury 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.[3] Bedrock rich in arsenic gives 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 the North American setting is another good example of environmental contamination.

Metals have been used as instruments of murder. 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 Germans during World War II in anticipation of a reinitiation of gas 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.

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


View Table

See Table

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.

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 habitation 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.[7]

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.[8] The US Centers for Disease Control and Prevention (CDC) Advisory Committee on Childhood Lead Poisoning Prevention released a report on February 8, 2013 that estimates that approximately 500,000 children aged 1-5 have blood lead levels that exceed 5 μg/dL. This is the level at which the CDC recommends that public health actions be initiated.[7]

There has been a significant reduction in blood lead levels of children younger than 5 years since the 1970s. This is largely the result of the US Environmental Protection Agency phasing out leaded gasoline from 1973-1995. As the average lead blood level from 1976-1980 was 16.5 5 μg/dL.[9]

Lead exposure in the adult population is more commonly found to be occupational, namely in mining, manufacturing, and construction. The CDC defines an elevated blood level of lead in adults to be above 25 μg/dL. In 2007, 6463 (76.7%) of elevated blood levels were found to be the result of occupational exposure.[10] In 2011, there were 2151 reported exposures to lead. Of these exposures, 1023 were reported to be in children younger than 5 years, and 643 were older than 20 years.[11]

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.[12] 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.[13]

According to the American Association of Poison Control Centers' (AAPCC) National Poisoning Data System (NPDS), in 2011, there were 775 human exposures related to arsenic (excluding pesticides) and 67 exposures related to arsenic-containing pesticides.[11]

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 accidentally ingest iron-containing tablets.[14] In adults, ingestion is largely intentional.

In 2011, there were 3777 reported exposures to iron and iron salts (not including iron-supplemented multivitamins). There were 2171 exposures in children younger than 5 years 1025 exposures in adults older than 20 years. There were 68 reported exposures to multivitamins that contained iron. Of these exposures, 43 were in children younger than 5 years and 18 were in adults older than 20 years.[11]

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.[15]

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.[16]

In 2011, there were 1575 exposures to mercury (excluding thermometers). Of these exposures, 155 were in children aged 5 years or younger and 752 were in adults older than 20 years. There were 2268 exposures to mercury-containing thermometers. In children aged 5 years or younger, there were 595 exposures, and 646 exposures occurred in adults aged 20 years and older.[11]

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 gear (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.[17, 18] 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.

Chronic arsenic toxicity is epidemic in Bangladesh and contiguous areas of the Indian subcontinent, where arsenic is an important component of bed-rock. 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.

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

Race

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.

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 accidental exposures.

History

Physical

Laboratory Studies

Imaging Studies

Other Tests

Emergency Department Care

Consultations

If intentional ingestion or overdose is suspected, place the patient in a closely monitored unit and consult a medical toxicologist and psychiatrist.

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.

Dimercaprol (British Anti-Lewisite; BAL)

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. May be given to patients with renal failure.

Edetate calcium disodium (Calcium Disodium Versenate)

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.

Penicillamine (Cuprimine, Depen)

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

Class Summary

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

Further Inpatient Care

Further Outpatient Care

Complications

Author

Adefris Adal, MD, MS, Clinical Assistant Instructor, Resident Physician, Department of Emergency Medicine, Kings County Hospital Center, State University of New York Downstate Medical Center

Disclosure: Nothing to disclose.

Coauthor(s)

Sage W Wiener, MD, Assistant Professor, Department of Emergency Medicine, State University of New York Downstate Medical Center; Assistant Director of Medical Toxicology, Department of Emergency Medicine, Kings County Hospital Center

Disclosure: Nothing to disclose.

Specialty Editors

Mark Louden, MD, Assistant Professor of Clinical Medicine, Division of Emergency Medicine, Department of Medicine, University of Miami, Leonard M Miller School of Medicine

Disclosure: Nothing to disclose.

John T VanDeVoort, PharmD, Regional Director of Pharmacy, Sacred Heart and St Joseph's Hospitals

Disclosure: Nothing to disclose.

John G Benitez, MD, MPH, Associate Professor, Department of Medicine, Medical Toxicology, Vanderbilt University Medical Center; Managing Director, Tennessee Poison Center

Disclosure: Nothing to disclose.

John D Halamka, MD, MS, Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center

Disclosure: Nothing to disclose.

Chief Editor

Asim Tarabar, MD, Assistant Professor, Director, Medical Toxicology, Department of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital

Disclosure: Nothing to disclose.

Additional Contributors

Richard H Sinert, DO Associate Professor of Emergency Medicine, Clinical Assistant Professor of Medicine, Research Director, State University of New York College of Medicine; Consulting Staff, Department of Emergency Medicine, Kings County Hospital Center

Richard H Sinert, DO is a member of the following medical societies: American College of Physicians and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Samara Soghoian, MD, MA Clinical Assistant Professor of Emergency Medicine, New York University School of Medicine, Bellevue Hospital Center

Samara Soghoian, MD, MA is a member of the following medical societies: American Academy of Clinical Toxicology, American College of Medical Toxicology, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

References

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Metal Acute Chronic Toxic Concentration Treatment
ArsenicNausea, vomiting,

"rice-water" diarrhea,

encephalopathy,

MODS, LoQTS,

painful neuropathy

Diabetes,

hypopigmentation/ hyperkeratosis,

cancer: lung, bladder, skin, encephalopathy

24-h urine:

≥50 µg/L urine, or

100 µg/g creatinine

BAL (acute, symptomatic)

Succimer

DMPS (Europe)

BismuthRenal failure; acute tubular necrosisDiffuse myoclonic encephalopathyNo clear reference standard*
CadmiumPneumonitis (oxide fumes)Proteinuria, lung cancer, osteomalaciaProteinuria and/or ≥15 µg/ g creatinine*
ChromiumGI hemorrhage, hemolysis, acute renal failure (Cr6+ ingestion)Pulmonary fibrosis, lung cancer (inhalation)No clear reference standardNAC (experimental)
CobaltBeer drinker’s (dilated) cardiomyopathyPneumoconiosis (inhaled); goiterNormal excretion:

0.1-1.2 µg/L (serum)

0.1-2.2 µg/L (urine)

NAC

CaNa2 EDTA

CopperBlue vomitus, GI irritation/ hemorrhage, hemolysis, MODS (ingested); MFF (inhaled)vineyard sprayer’s lung (inhaled); Wilson disease (hepatic and basal ganglia degeneration)Normal excretion:

25 µg/24 h (urine)

BAL

D-Penicillamine

Succimer

IronVomiting, GI hemorrhage, cardiac depression, metabolic acidosisHepatic cirrhosisNontoxic: < 300 µg/dL

Severe: >500 µg/dL

Deferoxamine
LeadNausea, vomiting, encephalopathy (headache, seizures, ataxia, obtundation)Encephalopathy, anemia, abdominal pain, nephropathy, foot-drop/ wrist-dropPediatric: symptoms or [Pb] ≥45 µ/dL (blood); Adult: symptoms or [Pb] ≥70 µ/dL[4] BAL

CaNa2 EDTA

Succimer

ManganeseMFF (inhaled)Parkinson-like syndrome,

respiratory, neuropsychiatric[5]

No clear reference standard*
MercuryElemental (inhaled): fever, vomiting, diarrhea, ALI;

Inorganic salts (ingestion): caustic gastroenteritis

Nausea, metallic taste, gingivo-stomatitis, tremor, neurasthenia, nephrotic syndrome; hypersensitivity (Pink disease)Background exposure "normal" limits:

10 µg/L (whole blood); 20 µg/L (24-h urine)

BAL

Succimer

DMPS (Europe)

NickelDermatitis; nickel carbonyl: myocarditis, ALI, encephalopathyOccupational (inhaled): pulmonary fibrosis, reduced sperm count, nasopharyngeal tumorsExcessive exposure:

≥8 µg/L (blood)

Severe poisoning:

≥500 µg/L (8-h urine)

*
SeleniumCaustic burns, pneumonitis, hypotensionBrittle hair and nails, red skin, paresthesia, hemiplegiaMild toxicity: [Se] >1mg/L (serum); Serious: >2 mg/L*
SilverVery high doses: hemorrhage, bone marrow suppression, pulmonary edema, hepatorenal necrosisArgyria: blue-grey discoloration of skin, nails, mucosaeAsymptomatic workers have mean [Ag] of 11 µg/L (serum) and 2.6 µg/L (spot urine)Selenium, vitamin E (experimental)
ThalliumEarly: Vomiting, diarrhea, painful neuropathy, coma, autonomic instability, MODSLate findings: Alopecia, Mees lines, residual neurologic symptomsToxic: >3 µg/L (blood)MDAC

Prussian blue

Zinc[6] MFF (oxide fumes); vomiting, diarrhea, abdominal pain (ingestion)Copper deficiency: anemia, neurologic degeneration, osteoporosisNormal range:

0.6-1.1 mg/L (plasma)

10-14 mg/L (red cells)

*
*No accepted chelation regimen; contact a medical toxicologist regarding treatment plan.

MODS, multi-organ dysfunction syndrome; LoQTS, long QT syndrome; ALI, acute lung injury; ATN, acute tubular necrosis; ARF, acute renal failure; DMPS, 2,3-dimercapto-1-propane-sulfonic acid; CaNa2 EDTA, edetate calcium disodium; MDAC, multi-dose activated charcoal; NAC, N -acetylcysteine.