Heavy Metal Toxicity 

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. 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. 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 (Open Table in a new window)

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.

Frequency

United States

Of the heavy metals, toxicity by chronic lead exposure is the most commonly encountered. The National Health and Nutrition Examination Survey (NHANES III) conducted from 1988-1990 found that 0.4% of persons aged 1 year and older had blood levels of lead of 25 mcg/dL or higher. The data also noted that, among those aged 1-5 years, an estimated 1.7 million children had blood levels greater than 10 mcg/dL. The syndrome of childhood plumbism caused by the ingestion of lead is believed to affect more than 2 million American preschool-aged children. Lead toxicity has a significantly higher prevalence among the African American population and in lower socioeconomic areas. Reliable figures for the prevalence of mercury and arsenic toxicities are not available. These toxidromes are usually encountered after industrial exposures. However, arsenic exposure often occurs outside the industrial realm because of its uses as a rodenticide and as a commonly used homicidal and suicidal agent.

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.^{[4, 5]} 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

• Little or no difference in prevalence exists.
• 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 accidental 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. A new 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.^[6]