from Harrison's Principles of Internal Medicine

Author: Howard Hu, M.D.
Professor of Occupational & Environmental Medicine
Harvard School of Public Health

Metals constitute a major category of toxins that pose a significant threat to health through occupational as well as environmental exposures. One indication of their importance relative to other potential hazards is their ranking by the U.S. Agency for Toxic Substances and Disease Registry, which lists all hazards present in toxic waste sites according to their prevalence and the severity of their toxicity.

The first, second, third, and sixth hazards on the list are heavy metals: lead, mercury, arsenic, and cadmium, respectively.

The atomic stability of metals allows their relatively easy tracing and measurement in biologic material, although the clinical significance of the levels measured is not always clear. Metals are inhaled primarily as dusts and fumes (the latter defined as tiny particles generated by combustion). Metal poisoning can also result from exposure to vapors (e.g., mercury vapor in the manufacture of fluorescent lamps). [Dr. Dooley's note: We must not forget the most important mercury vapor source - dental amalgams, also known as “silver” fillings!] When metals are ingested in contaminated food or drink or through hand-to-mouth activity (implicated especially often in children), their gastrointestinal absorption varies greatly with the specific chemical form of the metal and the nutritional status of the host.

Once a metal is absorbed, blood is the main medium for its transport, with the precise kinetics dependent on diffusibility, binding forms, rates of biotransformation, availability of intracellular ligands, and other factors. Some organs (such as bone, liver, and kidney) sequester metals in relatively high concentrations for years. Most metals are excreted through renal clearance and gastrointestinal excretion; some proportion is also excreted through salivation, perspiration, exhalation, lactation, skin exfoliation, and loss of hair and nails.

Some metals, such as copper and selenium, are essential to normal metabolic function as trace elements but are toxic at high levels of exposure. Others, such as lead and mercury, are theoretically capable of exerting toxic effects at any level of exposure. Indeed, much research is currently focused on the contribution of certain low-level metal exposure to chronic diseases and to subtle changes in health that may have significant public health consequences.

The most important component of treatment for metal toxicity is the termination of exposure. Another component is the use of chelating agents, which are used to bind metals into stable cyclic compounds with relatively low toxicity and to enhance their excretion.

The principal chelating agents are dimercaprol (British Anti-Lewisite, BAL), edetate (EDTA), succimer (DMSA, dimercaptosuccinic acid), and penicillamine; their specific use depends on the metal involved and the clinical picture. Activated charcoal does not bind metals and thus is of limited usefulness in cases of acute metal ingestion.

Besides the metals mentioned above, Aluminum contributes to the encephalopathy occurring in patients with severe renal disease who are undergoing dialysis. High levels of aluminum are found in the neurofibrillary tangles in the cerebral cortex and hippocampus of patients with Alzheimer's disease as well as in the drinking water and soil of areas with an unusually high incidence of Alzheimer's disease. The experimental and epidemiological evidence for the aluminum-Alzheimer's disease link is so far relatively weak, however, and it cannot be concluded that aluminum is a causal agent or a contributing factor in neurodegenerative disease.

Chromium is corrosive and sensitizing. Workers in the chromate and chrome pigment production industries have consistently had an excess risk of lung cancer. The introduction of cobalt chloride as a fortifier in beer led to outbreaks of fatal cardiomyopathy among heavy consumers.

Occupational exposure (e.g., of some miners, dry-battery manufacturers, and arc welders) to manganese can cause a Parkinsonian syndrome within 1 to 2 years, including gait disorders; postural instability; a masked, expressionless face; tremor; and psychiatric symptoms. With the introduction of methylcyclopentadienyl manganese tricarbonyl (MMT) as a gasoline additive, concern has arisen over the toxic potential of environmental manganese exposure.

Nickel exposure induces an allergic response, and inhalation of nickel compounds with low aqueous solubility (such as nickel subsulfide and nickel oxide) in occupational settings is associated with an increased risk of cancer of the lung.

Overexposure to selenium may cause local irritation of the respiratory system and eyes, gastrointestinal irritation, liver inflammation, loss of hair, depigmentation, and peripheral nerve damage.

Workers exposed to certain organic forms of tin (particularly trimethyl and triethyl derivatives) have developed psychomotor disturbances, including tremor, convulsions, hallucinations, and psychotic behavior.

Finally, thallium, which is a component of some insecticides, metal alloys, and fireworks, is absorbed through the skin as well as through ingestion and inhalation. Severe poisoning follows a single ingested dose of >1 g or >8 mg/kg. Nausea and vomiting, abdominal pain, and hematemesis precede confusion, psychosis, organic brain syndrome, and coma. Thallium is radiopaque. Induced emesis or gastric lavage is indicated within 4 to 6 hours of acute ingestion; Prussian blue prevents absorption and is given orally at 250 mg/kg in divided doses. Unlike other types of metal poisoning, thallium poisoning may be less severe when activated charcoal is used to interrupt its enterohepatic circulation. Other measures include forced diuresis, treatment with potassium chloride (which promotes renal excretion of thallium), and peritoneal dialysis.

Lead has been mined and used in industry and in household products for centuries. The dangers of lead toxicity, the clinical manifestations of which are termed plumbism, have been known since ancient times. The twentieth century saw both the greatest-ever exposure of the general population to lead and an extraordinary amount of new research on lead toxicity.

Populations are exposed to lead chiefly via paints, cans, plumbing fixtures, and leaded gasoline. The intensity of these exposures, while decreased by regulatory actions, remains high in some segments of the population because of the deterioration of lead paint used in the past and the entrainment of lead from paint and vehicle exhaust into soil and house dust. Many other environmental sources of exposure exist, such as leafy vegetables grown in lead-contaminated soil, improperly glazed ceramics, lead crystal, and certain herbal folk remedies. Many industries, such as battery manufacturing, demolition, painting and paint removal, and ceramics, continue to pose a significant risk of lead exposure to workers and surrounding communities.

New research on lead toxicity has been stimulated by advances in toxicology and epidemiology as well as by a shift of emphasis in toxicology away from binary outcomes (life/death; 50% lethal dose) to grades of function, such as neuropsychological performance, indices of behavior, blood pressure, and kidney function.

Tests for levels of lead in blood have facilitated both research on lead and surveillance of individuals at risk. Blood lead is now measured with stringent quality controls in commercial laboratories throughout the United States. Measurement of the blood lead levels of children 6 months to 5 years of age is mandated by some states, and the U.S. Occupational Safety and Health Administration (OSHA) requires the testing of workers who may be exposed to lead in the course of their jobs.