Toxicity Associated with Arsenic

At a Glance

Heavy metal toxicity should be considered in any patient presenting with renal disease of unexplained origin, bilateral neuropathy, acute changes in mental function, or a history of exposure (such as occupational exposure).

Arsenic is probably the best known of the metal toxins. It targets the gastrointestinal (GI) tract, skin, bone marrow, kidneys, and peripheral nervous system. The presenting symptoms depend on the route and length of exposure. However, in general, patients present with nausea and vomiting, unexplained sudden weight loss, abdominal pain, diarrhea, headache, fever, lower extremity peripheral neuropathy, deteriorating liver and kidney function, garlic smelling urine, leukopenia, and thrombocytopenia.

Arsenic exists in a number of toxic and non-toxic forms. The toxic forms are the inorganic species, As (III) and As (V), and their partially detoxified metabolites, monomethylarsine (MMA) and dimethylarsine (DMA). Arsine gas (AsH3) is also toxic and is generated when acids combine with arsenic containing metals.

The largest source of toxic arsenic exposure in the environment is pesticides. Organic or non-toxic arsenic exposure occurs primarily through direct consumption of food. The average adult consumes approximately 30 mcg/kg/day of dietary intake from food items, such as seafood.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Heavy metal toxicity is not common (prevalence is similar to inborn errors of metabolism), and diagnosis can be difficult, because the signs and symptoms are similar to many other diseases. Despite these facts, screening for heavy metal toxicity is indicated in all patients with symptoms suggestive of toxicity, as screening is relatively simple and treatment that reduces long-term morbidity is available.

A 24-hour urine is the specimen of choice for assessing arsenic toxicity, because arsenic concentrates in the kidney. Significant exposure is considered greater than 1000 mcg/24-hour urine specimen. The toxic inorganic forms, As(V) and As(III), are found in the urine shortly after ingestion (peaking at 10 hours and returning to normal at 20-30 hours after ingestion), whereas the metabolites monomethylarsine (MMA) and dimethylarsine (DMA) predominate after 24 hours (peaking at 40-60 hours and returning to normal within 6-20 days).

Nail and hair (axillary or pubic) specimens are preferred to assess long-term (6 months to 1 year) arsenic exposure, because they contain the highest arsenic content. The high arsenic content in hair and nails is due to the high affinity of arsenic for keratin and the covalent complexes that form between arsenic and the sulhydryl groups in the cysteines of keratin. Nail or hair arsenic greater than 1.00 mcg/g dry weight indicates excessive exposure.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

Because of the presence of organic (i.e., nontoxic) arsenic in food, normal patients can have up to 20 mcg of arsenic per 24 hour urine specimen. Although organic arsenic is rapidly excreted, certain foods, such as seafood, with higher arsenic concentrations should be avoided for at least 48-72 hours prior to urine collection, as falsely elevated results (sometimes in the toxic range of 350 mcg/day) can be obtained.

Medications and nutritional supplements may also introduce interfering substances. After consultation with a physician, patients should be encouraged to discontinue nutritional supplements, vitamins, minerals, and nonessential over-the-counter medications for 48-72 hours prior to specimen collection.

Nitric acid should not be added to the collection container, because it may cause assay failure. Many laboratories test for its presence prior to analysis and report the specimen as unsatisfactory when nitric acid is detected.

What Lab Results Are Absolutely Confirmatory?

Heavy metal toxicity can be confirmed if three factors are present: a source of metal exposure is evident, the patient demonstrates signs and symptoms of toxicity with that metal, and an abnormal concentration of that metal is present in blood, urine, or tissue.

The most sensitive and specific methods to measure total arsenic in biological fluids are atomic absorption spectrometry (AAS) and inductively coupled plasma-mass spectrometry (ICP-MS). Although AAS is simpler and less expensive, ICP-MS has a higher throughput and allows for analysis of several toxic metals simultaneously.

Because of the various forms and different associated toxicities, total urine arsenic is only partially useful for assessment of exposure. Methods, such as HPLC or LC-MS/MS, that can provide arsenic speciation in biological fluids and tissues to distinguish between inorganic and organic (from food) forms are the most accurate for determination of arsenic toxicity. These methods typically report the total arsenic concentration along with the percentage of organic and inorganic species. There is no limit to the normal range for organic forms of arsenic, whereas inorganic arsenic concentrations greater than or equal to 25 mcg are considered toxic. However, arsenic speciation methods are complex and are performed by a limited number of laboratories.

What Are Additional Issues of Clinical Importance?

Arsenic toxicity is due to three different mechanisms, two of which are related to energy transfer. Arsenic binds to dihydrolipoic acid, a necessary cofactor for pyruvate dehydrogenase, inhibits gluconeogenesis, and results in loss of energy supply to anaerobic cells, such as neural cells that rely on anaerobice respiration for energy. This leads to bilateral peripheral neuropathy. Arsenic also competes with phosphate for reaction with ADP, resulting in formation of lower energy ADPs, rather than ATP resulting in loss of energy supply to aerobic cells, such as cardiac cells. Finally, arsenic binds to hydrate sulfhydryl groups on proteins distorting structure and leading to loss of activity. This primarily affects the GI tract and proximal tubules of the kidney.

Arsenic toxicity is treated by removing the source of exposure, supportive care, and chelation therapy with drugs, such as 2,3-dimercaptosuccinic acid.

Errors in Test Selection and Interpretation

Whole blood, serum, and plasma are the least useful specimens for identifying arsenic exposure, because arsenic rapidly (<4 hours) disappears into the phosphate pool and tissue proteins.

High concentrations of gadolinium and iodine are known to interfere with most testing for heavy metals. If either gadolinium- or iodine-containing contrast media have been administered within 96 hours of specimen collection, results are not valid and should be repeated more than 96 hours after administration of a contrast media containing gadolinium or iodine.

ICP-MS has well-known interferents, namely 40Ar35Cl, and strategies must be employed to correct for this interference to avoid test misinterpretation.