Clinical Information

Arsenic:

Arsenic (As) exists in many toxic and nontoxic forms. The toxic forms are the inorganic species As(5+), also denoted as As(V), the more toxic As(3+), also known as As(III), and their partially detoxified metabolites, monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA). Detoxification occurs in the liver as As(3+) is oxidized to As(5+) and then methylated to MMA and DMA. As a result of these detoxification steps, As(3+) and As(5+) are found in the urine shortly after ingestion, whereas MMA and DMA are the species that predominate more than 24 hours after ingestion.

Blood concentrations of arsenic are elevated for a short time after exposure, after which arsenic rapidly disappears into tissues because if its affinity for tissue proteins. The body treats arsenic like phosphate, incorporating it wherever phosphate would be incorporated. Arsenic "disappears" into the normal body pool of phosphate and is excreted at the same rate as phosphate (excretion half-life of 12 days). The half-life of inorganic arsenic in blood is 4 to 6 hours, and the half-life of the methylated metabolites is 20 to 30 hours. Abnormal blood arsenic concentrations (>12 ng/mL) indicate significant exposure but will only be detected immediately after exposure. Arsenic is not likely to be detected in blood specimens drawn more than 2 days after exposure because it has become integrated into nonvascular tissues. Consequently, blood is not a good specimen to screen for arsenic, although periodic blood levels can be determined to follow the effectiveness of therapy. Urine is the preferred specimen for assessment of arsenic exposure.

A wide range of signs and symptoms may be seen in acute arsenic poisoning, including headache, nausea, vomiting, diarrhea, abdominal pain, hypotension, fever, hemolysis, seizures, and mental status changes. Symptoms of chronic poisoning, also called arseniasis, are mostly insidious and nonspecific. The gastrointestinal tract, skin, and central nervous system are usually involved. Nausea, epigastric pain, colic (abdominal pain), diarrhea, and paresthesias of the hands and feet can occur.

Lead:

Lead is a heavy metal commonly found in the environment that can be an acute and chronic toxin.

Lead was banned from household paints in 1978 but is still found in paint produced for nondomestic use and in artistic pigments. Ceramic products available from noncommercial suppliers (such as local artists) often contain significant amounts of lead that can be leached from the ceramic by weak acids, such as vinegar and fruit juices. Lead is found in dirt from areas adjacent to homes painted with lead-based paints and highways where lead accumulates from use of leaded gasoline. Use of leaded gasoline has diminished significantly since the introduction of nonleaded gasolines, which have been required in personal automobiles since 1972. Lead is found in soil near abandoned industrial sites where lead may have been used. Water transported through lead or lead-soldered pipe will contain some lead with higher concentrations found in water that is weakly acidic. Some foods (for example: moonshine distilled in lead pipes) and some traditional home medicines contain lead.

The typical diet in the United States contributes 1 to 3 mcg of lead per day, of which 1% to 10% is absorbed; children may absorb as much as 50% of the dietary intake, and the fraction of lead absorbed is enhanced by nutritional deficiency. The majority of the daily intake is excreted in the stool after direct passage through the gastrointestinal tract. While a significant fraction of the absorbed lead is rapidly incorporated into bone and erythrocytes, lead ultimately distributes among all tissues, with lipid-dense tissues, such as the central nervous system, being particularly sensitive to organic forms of lead. All absorbed lead is ultimately excreted in the bile or urine. Soft-tissue turnover of lead occurs within approximately 120 days.

Lead expresses its toxicity by several mechanisms. It avidly inhibits aminolevulinic acid dehydratase and ferrochelatase, 2 of the enzymes that catalyze synthesis of heme; the end result is decreased hemoglobin synthesis resulting in anemia. Lead also is an electrophile that avidly forms covalent bonds with the sulfhydryl group of cysteine in proteins. Thus, proteins in all tissues exposed to lead will have lead bound to them. The most common sites affected are epithelial cells of the gastrointestinal tract and of the kidney.

Avoidance of exposure to lead is the treatment of choice. However, chelation therapy is available to treat severe disease. Oral dimercaprol may be used in the outpatient setting except in the most severe cases.

Cadmium:

The toxicity of cadmium resembles the other heavy metals (arsenic, mercury, and lead) in that it attacks the kidney; kidney dysfunction with proteinuria with slow onset (over a period of years) is the typical presentation.

Breathing the fumes of cadmium vapors leads to nasal epithelial deterioration and pulmonary congestion resembling chronic emphysema.

The most common source of chronic exposure comes from spray painting of organic-based paints without use of a protective breathing apparatus; auto repair mechanics represent a susceptible group for cadmium toxicity. In addition, another common source of cadmium exposure is tobacco smoke.

Mercury:

Mercury (Hg) is relatively nontoxic in its elemental form. If Hg(0) is chemically modified to the ionized, inorganic species, Hg(2+), it becomes toxic. Further bioconversion to an alkyl Hg, such as methyl Hg (CH3Hg[+]), yields a species of mercury that is highly selective for lipid-rich tissue such as neurons and is very toxic. The relative order of toxicity is:

Least Toxic -- Hg(0) < Hg(2+) << [CH3Hg](+) -- Very Toxic

Mercury can be chemically converted from the elemental state to the ionized state. In industry, this is frequently done by exposing Hg(0) to strong oxidizing agents, such as chlorine.

Hg(0) can be bioconverted to both Hg(2+) and alkyl Hg by microorganisms that exist in the normal human gut as well as in the bottom sediment of lakes, rivers, and oceans. When Hg(0) enters bottom sediment, it is absorbed by bacteria, fungi, and small microorganisms; they metabolically convert it to Hg(2+), CH3Hg(+), and C2H6Hg. Should these microorganisms be consumed by larger marine animals and fish, the mercury passes up the food chain in the rather toxic form.

Mercury expresses its toxicity in 3 ways:

-Hg(2+) is readily absorbed and reacts with sulfhydryl groups of protein, causing a change in the tertiary structure of the protein-a stereoisomeric change-with subsequent loss of the unique activity associated with that protein. Because Hg(2+) becomes concentrated in the kidney during the regular clearance processes, this target organ experiences the greatest toxicity.

-With the tertiary change noted previously, some proteins become immunogenic, eliciting a proliferation of T lymphocytes that generate immunoglobulins to bind the new antigen; collagen tissues are particularly sensitive to this.

-Alkyl Hg species, such as CH3Hg(+), are lipophilic and avidly bind to lipid-rich tissues, such as neurons. Myelin is particularly susceptible to disruption by this mechanism.

Members of the public will occasionally become concerned about exposure to mercury from dental amalgams. Restorative dentistry has used a mercury-silver amalgam for approximately 90 years as a filling material. A small amount of mercury (2-20 mcg/day) is released from a dental amalgam when it was mechanically manipulated, such as by chewing. The habit of gum chewing can cause release of mercury from dental amalgams greatly above normal. The normal bacterial microbiota present in the mouth converts a fraction of this to Hg(2+) and CH3Hg(+), which was shown to be incorporated into body tissues. The World Health Organization safety standard for daily exposure to mercury is 45 mcg/day. Thus, if one had no other source of exposure, the amount of mercury released from dental amalgams is not significant.(1) Many foods contain mercury. For example, commercial fish considered safe for consumption contain less than 0.3 mcg/g of mercury, but some game fish contain more than 2.0 mcg/g and, if consumed on a regular basis, contribute to significant body burdens.

Therapy is usually monitored by following urine output; therapy may be terminated after urine excretion is below 50 mcg/day.