Heavy Metal Toxicity

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 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, so 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 central nervous system (CNS), peripheral nervous system (PNS), and the gastrointestinal, hematopoietic, renal, and cardiovascular (CV) systems. 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.

A literature review by Giulioni et al indicated that heavy metal exposure is strongly associated with male infertility. According to the evidence, sperm concentration, motility, and morphology are negatively impacted by lead exposure, for the most part via oxidative stress and enzymatic inhibition. Cadmium exposure can produce sperm abnormalities through disruption of the blood-testis barrier and acrosomal function, while oxidative stress, apoptosis, and damage to sperm motility have been associated with arsenic exposure. ^[8]

Frequency

United States

In 2023, according to the 41st Annual Report of the National Poison Data System (NPDS) from America's Poison Centers, there were 7905 single-substance exposures to heavy metals (not including iron or arsenic-including pesticides). Of those, 2348 were reported in children aged 5 years or younger, 1013 were reported in children aged 6-19, and 3599 were reported in persons aged 20 years or older. ^[9]

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. Between 1998 and 1999, “either an interior lead dust hazard or an interior deteriorated lead-based paint hazard” occurred in the homes of 22% of US children aged 0-5 years, with this proportion having declined to 15% in 2005-2006. ^[10]

Evidence has shown that lead blood levels of less than 10 μg/dL have adverse neurodevelopmental outcomes in children younger than 5 years. ^[11] According to the US Centers for Disease Control and Prevention (CDC), an estimated 500,000 US children aged 1-5 years have blood lead levels of 3.5 μg/dL or higher, with 3.5 μg/dL being the level at which the CDC recommends that public health actions be initiated for youngsters in this age group. ^{[12, 13]}

In children aged 1-5 years, the median blood lead level fell from 15 µg/dL in 1976-1980 to 0.6 µg/dL in 2017 to March 2020, a 96% reduction. The largest declines in blood lead levels corresponded with the US Environmental Protection Agency phasing out leaded gasoline from 1973-1995. ^[10]

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 of 10 μg/dL or greater 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 4547 adults with blood lead levels of 25 μg/dL or greater who had a known lead exposure history, 93.7% had occupational exposure ^[14]

In 2023, according to the NPDS, there were 2349 single-substance exposures to lead. This included 1214 reported in children aged 5 years or younger, 283 reported in children aged 6-19 years, and 653 in persons aged 20 years or older. ^[9]

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]

In 2023, according to the NPDS, there were 749 single-substance exposures to arsenic (excluding pesticides), including 557 reported in persons aged 20 years or older. There were also 12 single-substance exposures to arsenic-containing pesticides. ^[9]

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 2023, according to the NPDS, there were 5780 single-substance exposures to iron and iron salts (not including iron-supplemented multivitamins). Of those, 2380 were reported in children aged 5 years or younger, 1017 were reported in children aged 6-19 years, and 2105 were reported in persons aged 20 years or older. ^[9]

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 2023, according to the NPDS, there were 872 single-substance exposures to elemental mercury (excluding thermometers). This included 49 reported in children aged 5 years or younger, 109 reported in children aged 6-19 years, and 530 reported in persons aged 20 years or older. Also that year there were 793 single-substance exposures to mercury-containing thermometers, including 117 reported in children aged 5 years or younger, 90 reported in children aged 6-19 years, and 390 reported in persons aged 20 years or older. In addition, there were 275 other single-substance mercury exposures in 2023, including 201 reported in persons aged 20 years or older. ^[9]

International

Heavy metal toxicity has emerged as a significant occupational hazard associated with electronics recycling in China and Southeast 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. As previously discussed, 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.

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, possibly 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 are more strongly associated with cognitive and behavior development than are blood lead concentrations measured in children aged 2 years. ^[23]

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.

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. ^[24]

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