Introduction

Heavy metal is a broad term used to describe a group of naturally occurring metallic elements of high molecular weight and density when compared to water.[1] At low concentrations, certain heavy metals, such as iron, zinc, copper, and manganese, are essential for human survival but can become toxic agents at higher concentrations. Other heavy metals, such as arsenic, cadmium, lead, thallium, and mercury, serve no biological role. However, they will inevitably enter the human body due to their presence in the environment. Similarly to the essential metals, they will induce toxicity once certain concentrations are reached. 

Etiology and Epidemiology

Heavy metal toxicity is typically secondary to occupational exposure, such as mining and metallurgy, or from contact with industrial waste, either directly or through contaminated food and water sources. Shellfish can be of particular concern. Polluted runoff can cause heavy metals to accumulate in shellfish that are then consumed by humans.[1][2] Aware of the increased health risk for workers, the Occupational Health and Safety Administration (OSHA) sets maximum exposure limits over a set period of time for employees. In addition, the Environmental Protection Agency (EPA) monitors these heavy metal pollutants in the environment and sets acceptable limits for exposure amongst the general population.

Medications and supplements can also be of concern. While supplements of essential metals can be necessary for patients with deficiencies, inappropriate use could lead to clinical manifestations. Other supplements may have unknown amounts of metals, such as the case with ayurvedic medicines. One study found 65% of ayurvedic medicines contained lead while one third contained arsenic and mercury.[3]

Other specific sources of common heavy metals are listed below:

Arsenic: Inorganic arsenic, the toxic form of arsenic, is most commonly ingested from contaminated water and food. Sources of contamination include pesticides, smelting processes of copper and lead, wood preservatives, and volcanic eruptions. 

Lead: Leaded paint from older homes and lead leaching from pipes can still be a major source.[1][4] One of the most well-known incidences is lead poisoning in Flint, Michigan, from contaminated drinking water. Other sources include firing ranges, battery manufacturing, and cosmetics.

Cadmium: Smoking is a significant source of cadmium.[5] Others include vegetables, seeds, shellfish, plastics production, and nickel-cadmium battery manufacturing.  

Mercury: The most common source of mercury is methylmercury found in fish secondary to pollution. Mercury is also an occupational hazard for dentists in countries where the production of amalgam (filling material for cavities), is still allowed.[6]  

Thallium: Sources include coal combustion, semiconductor manufacturing, and exhaust emissions.

Pathophysiology

The general mechanism of heavy metal toxicity results from disruption of metabolic homeostasis at a cellular level. This results from an excess of the heavy metal in the body, leading to deposition and accumulation in various tissues. The metallic deposits then hinder biological function via enzymatic, metabolic, and mitochondrial interference.[7] The extent of this dysfunction and subsequent damage depends on the pharmacokinetics of each individual metal and route of exposure.

Specimen Requirements and Procedure

Testing for heavy metal exposure can be done indirectly or directly. For example, a blood smear with basophilic stippling for a patient with blue lines at the base of the gums would raise clinical suspicion for chronic lead toxicity. However, the direct, and thus, a confirmatory test for heavy metals is an analysis of the suspected metal concentration in the body.

Samples for testing can include blood, urine, hair, and nails. The specimen collected depends on the type of metal being tested and the onset of exposure. Most, but not all, heavy metals can be analyzed using a 24-hour urine collection for acute, chronic, and prior exposure. A urine spot test can be used, but creatinine concentrations should also be ordered.[8] Typically, a blood test will be ordered in conjunction with a urine metal analysis for acute and chronic exposures. 

Since metal concentrations are normally in the nano and microgram range, careful consideration needs to be taken to prevent contamination.[9][10] Specialized “trace element free” vials should be used. Blood samples should be taken using a royal blue-capped vial. The exception is lead in which a tan top lead-free tube is acceptable. Preferably, samples should be kept refrigerated.

Diagnostic Tests

The heavy metal concentrations are evaluated using an inductively coupled plasma with mass spectrometry (ICP/MS) or atomic absorption spectroscopy (AAS). ICP/MS is more commonly used due to its low detection limit and ability to detect multiple elements at once.[11] The Center for Disease Control’s Biomonitoring Program and the Agency for Toxic Substances and Disease Registry (ATSDR) provides pharmacokinetic data on heavy metals in different bodily fluids and organs that can be useful when determining which sample specimen to use: 

Arsenic: Inorganic arsenic has a half-life of about 3 to 4 hours in the blood. It’s major metabolites, monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA), will then be excreted into the urine and can be detected for 2 to 4 days.[12] Hair can also be used for detection for 6-12 months. Organic forms of arsenic, such as arsenobetaine, are relatively non-toxic forms of arsenic found in seafood. After consumption, organic arsenic can be present in both blood and urine at high concentrations and will be excreted from the body in urine after one to two days.[13][14] Therefore, when testing for acute arsenic toxicity, it is important to take into consideration any recent seafood consumption. In order to differentiate organic arsenic from inorganic arsenic for a heavy metal panel, an arsenic reflex to fractionated test can be ordered.[15]

Lead: A blood test is the most widely used method for lead detection. Following an exposure, lead has a half-life in the blood of about 1-2 months.   

Cadmium: Cadmium has a half-life in the blood of 3 to 4 months, making this option useful for recent exposure.[16] However, cadmium has a significantly high half-life of approximately 30 years in the body. This makes urine, hair, or nail analysis a good representation of the total body burden of cadmium. 

Mercury: Metallic and elemental mercury initially has a quick half-life of 3 days in blood and then a longer half-life of 1 to 3 weeks. A urine sample can also be used for 1 to 3 months post-exposure. On the other hand, methylmercury has a half-life of about 40-90 days in blood and hair samples.[17] A urine test should not be performed because roughly 90% of methylmercury is excreted through feces.[18] This makes a mercury urinalysis only useful for inorganic and elemental mercury.

Thallium: Thallium has a half-life of 3 days in blood. Urine can be used for 2 months post-exposure.

Testing Procedures

Heavy metals can be ordered as individual tests or metals can be tested simultaneously. The type of panels available depend on each laboratory but typically contain arsenic, cadmium, lead, and mercury. Determining which metals to test will be dependent on the clinician’s assessment of a patient’s clinical symptoms and potential exposures.

Interfering Factors

Seafood consumption should be avoided 48 hours prior to testing because of the prevalence of metals in seafood. Some laboratories may recommend iodine or gadolinium-based contrast not be used in the past 72 hours as these can potentially interfere with the results for certain metals, including selenium, platinum, zinc, and manganese.[19][20] Daily environmental exposures should be taken into consideration for hair and nail samples. For example, cadmium in cigarette smoke can bind to the outside of hair and nails, inaccurately presenting as a high cadmium concentration in the body. This can be minimized with proper preparation of samples in analytical labs.

Clinical Significance

The concentration of each heavy metal is given with a reference range provided by the testing laboratory. It is important to note that reference values may vary by the lab and geographically.[21][22] While an average concentration in the general population might be considered “normal,” this doesn’t imply that there are no health consequences at these concentrations. OSHA and EPA continuously change guidelines for acceptable exposure limits. Alternatively, an “abnormal” heavy metal screen does not automatically constitute toxicity. However, if presented with a higher than average metal concentration, further investigation should be done about possible sources of exposure and any presence of symptoms.

Enhancing Healthcare Team Outcomes

Heavy metal toxicity can present as general symptoms and therefore make diagnosis difficult. A thorough history is needed to determine if any environmental metal sources are present, especially for children, due to the long-term neurological effects that can occur. Routine heavy metal tests should be performed when a patient has an occupational exposure. Clinicians should consult their local poison control center or toxicologist if heavy metal toxicity is suspected. Working closely with public health officials can also provide insight into any local regulation violations leading to above-average metal concentrations in patients. Nurses and laboratory technologists should be trained in proper technique and handling of vials to minimize trace elemental contamination that can potentially interfere with results.