Arsenic exposure can lead to acute and chronic intoxication with variable organ dysfunction.

Epidemiology

• Main routes of exposure –  ingestion of arsenic-containing foods, water and beverages, or inhalation of contaminated air; therapeutic exposure may also result in toxicity
  • Arsenic is commonly found in fish and seafood and may also come from dietary supplements and well water
  • Several industries continue to use arsenic in the production of pesticides, preservatives, metal alloys, glasses, enamels, semiconductors and other items
  • Exposure controls are required for workers at risk; arsenic intoxication is rare, except in suicides or accidents
  • Arsenic trioxide (Trisenox^®) is an FDA-approved treatment in acute promyelocytic leukemia (APL) for relapse or for patients not achieving remission with standard chemotherapy

Toxicity

• Arsenic exists in >30 chemical forms or species that can be grouped into inorganic, methylated and organic fractions
  • Inorganic – occurs naturally in rocks, soil, and groundwater; also found in many synthetic products, poisons, and industrial processes
    • Toxic forms (trivalent and pentavalent) include arsenite or As(III) and arsenate or As(V)
  • Methylated – arises primarily from metabolism of inorganic species, but small amounts may arise directly from food
    • Toxic methylated compounds such as monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) are formed by hepatic metabolism of As(III) and As(V)
      • Methylated inorganic forms are considered less toxic than As(III) and As(V); however, they are eliminated more slowly (1-3 weeks)
  • Organic – arises primarily from food such as fish, seaweed and shellfish
    • Relatively nontoxic organic forms (primarily arsenobetaine and arsenocholine) which are cleared rapidly (1-2 days)
      • Arsenobetaine, the most prevalent arsenic species in seafood, is a common cause for increased total arsenic concentration in urine because it is excreted unchanged for 1-2 days

Clinical Presentation

• Relationship of clinical signs and symptoms to arsenic exposure depends on duration and extent of exposure to inorganic and/or methylated forms of arsenic and to the underlying clinical status of the patient
• Acute exposure
  • May result in death
  • Best detected by urine; however, if exposure occurred within 24 hours or if patient cannot provide a urine specimen (eg, dialysis patient), arsenic can be detected in blood  
  • Symptoms
    • Gastrointestinal – nausea, emesis, abdominal pain, rice-water diarrhea
    • Bone marrow – pancytopenia, anemia, basophilic stippling
    • Cardiovascular – EKG changes (torsades de pointes)
    • Central nervous system (CNS) – encephalopathy, polyneuropathy
    • Renal – renal insufficiency, renal failure
    • Hepatic – hepatitis
    • APL differentiation syndrome (APL patients receiving arsenic trioxide treatment)
      • Symptoms include fever, weight gain, pulmonary infiltrates, pleural or pericardial effusions
• Chronic exposure
  • Dermatologic – Mees lines, hyperkeratosis, hyperpigmentation, alopecia
  • Hepatic – cirrhosis, hepatomegaly
  • Cardiovascular – hypertension, peripheral vascular disease
  • Central nervous system – stocking glove neuropathy, tremor
  • Malignancies – skin (squamous cell), hepatocellular, bladder, lung, renal

Indications for Testing

• Known or suspected exposure to arsenic

Laboratory Testing

• Acute exposure
  • Due to the short half-life of arsenic in the blood, urine is the preferred specimen for detection of exposure
    • Elevated results will be fractionated to differentiate between toxic inorganic forms and relatively nontoxic organic forms
  • Very recent exposure (<24 hours) – serum testing may be helpful
• Chronic or past exposures (>3 weeks) – analysis of hair or nails is most useful in determining time of exposure
• The Biological Exposure Index (BEI) established by the American Conference of Governmental Industrial Hygienists (ACGIH) for the sum of inorganic arsenic and methylated metabolites of arsenic is 35 µg/L
  • Clinical symptoms may not be evident at 35 µg/L; toxic thresholds are not well established
  • For specimens with a total concentration between 35-2,000 µg/L, fractionation is performed to determine proportion of organic, inorganic and methylated forms
  • If low-level chronic poisoning is suspected, the µg/gCRT ratio may be more sensitive than total arsenic concentration
    • In some situations, it may be appropriate to fractionate specimens with a ratio >30 µg/gCRT despite a total arsenic concentration <35 µg/L

• Met287Thr polymorphism of AS3MT gene
  • Correlates with arsenic urinary profile
  • Increased MMA excretion, presumed reduced long-term toxicity from arsenic exposure

Tests generally appear in the order most useful for common clinical situations

General

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ARUP Institute for Clinical and Experimental Pathology®

• Bornhorst JA, Hunt JW, Urry FM, McMillin GA. Comparison of sample preservation methods for clinical trace element analysis by inductively coupled plasma mass spectrometry. Am J Clin Pathol. 2005; 123 (4) :578-583.PubMed

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