By Lee Cantrell, PharmD
Introduction
Arsenic is a naturally occurring element that is an odorless, tasteless, silver-grey, brittle, semi-metallic solid. When bound to sulfur, oxygen, and chlorine it forms inorganic compounds; when bound to molecules containing carbon it forms organic compounds. Arsenic compounds contain either trivalent (arsenite) or pentavalent (arsenate) forms. Inorganic and trivalent arsenic are the most toxic forms to humans. An acute ingestion of 100-200 mg of inorganic trivalent arsenic can be lethal. Chronically, doses of 400 mcg/day can increase the frequency of some cancers. Industrial uses of arsenic include: metallurgy, semiconductor and glass manufacturing, wood preservatives, pesticides and herbicides. Arsenic can be found in a variety of herbal and alternative medicinal remedies, and it is used in chemotherapy. Environmentally, arsenic contaminates water supplies in various parts of the world and bioaccumulates in marine animals and seaweed. Arsenic also has the nefarious distinction of being one of the most widely used homicidal poisons throughout history. Although cases are relatively rare in the United States, clinicians should be familiar with the pathophysiology, clinical effects, treatment, and pitfalls of arsenic poisoning.
Case presentation
A 42 year-old male was brought to the emergency department 90 minutes after intentionally ingesting the contents of arsenic-containing ant bait. Upon arrival, the patient complained of abdominal pain and was vomiting profusely. He was also lethargic, with tachycardia and hypotension. Intravenous fluid resuscitation was initiated, followed by intramuscular dimercaprol (BAL) administered every 6 hours. Over the next 12 hours, the patient’s symptoms improved and hemodynamic stability returned. A spot urine arsenic level was measured at 1141 mcg/L. On hospital day three, the patient was in stable condition, and was switched to oral succimer (DMSA) for additional chelation therapy and discharged. At follow-up six weeks later, the patient remained asymptomatic.
Questions
- What are the physiologic mechanisms by which arsenic exerts its effects?
- What spectrum of clinical symptoms can be expected following acute and chronic arsenic poisonings?
- How should arsenic poisoning be treated?
Epidemiology
In 2005, 969 cases of exposure to non-pesticide arsenic-containing substances were reported to the American Association of Poison Control Centers. The vast majority (76%) involved adults aged 19 years and older. Additionally, 371 cases of exposure to arsenic-containing pesticides were reported with 73% involving children less than 6 years old. For non-pesticide arsenic-containing substance cases, 54% were evaluated in a healthcare facility. Conversely, for arsenic-containing pesticides, only 12% of patients were evaluated in a healthcare facility. With respect to outcome, 7% of patients experienced moderate or major symptoms and one death was reported. Historically, reasons for arsenic poisoning include unintentional, environmental, occupational, iatrogenic, suicide and homicide. Both acute and chronic exposures have occurred with all of the aforementioned causes except suicide. Chronic exposure to arsenic-contaminated well water in Bangladesh is responsible for the largest mass poisoning in human history.
Pathophysiology
Arsenicals may be absorbed by inhalation, ingestion, and percutaneous absorption following prolonged contact. The toxicity of arsenic depends on its solubility, valence, and form (inorganic vs. organic). Trivalent arsenic (arsenite) is generally more toxic than pentavalent arsenic (arsenate), because it is more lipophillic and more readily absorbed. Arsenic is almost completely cleared from the blood within 2 hours to 7 days. The majority of a single dose of inorganic arsenic is excreted in the first few days after exposure, though complete urinary elimination may take several weeks. Arsenic’s volume of distribution is unknown, but be appears to be large. Trivalent arsenicals exert their toxic effects primarily by inhibiting sulfhydryl-containing enzyme dependent processes including glycolysis, the tricarboxylic acid (Krebs) cycle, gluconeogenesis and fatty acid oxidation. Pentavalent arsenicals are converted to trivalent arsenic in vivo and thus share similar toxicity, but they also inhibit oxidative phosphorylation. Both forms are known human carcinogens. With respect to organic arsenicals, such as those found in shellfish, there is no data to suggest that significant toxicity occurs with human exposure.
Clinical presentation
In acute arsenic toxicity, gastrointestinal symptoms occur within minutes-to-hours and may be followed by cardiovascular symptoms ranging from hypotension and sinus tachycardia, to complete cardiovascular collapse. Subsequent findings may include generalized weakness and myalgias, lethargy, QT prolongation, pulmonary edema, acute respiratory distress syndrome, hemolysis, rhabdomyolysis, acute renal failure and hepatitis. Delayed effects may include sensorimotor peripheral neuropathies, congestive cardiomyopathy, ventricular dysrhythmias, encephalopathy, and pancytopenia. With chronic toxicity, clinical findings may include malaise, weight loss, melanosis of the trunk and extremities, desquamation of the palms and soles of the feet, sensory-predominant peripheral neuropathy, peripheral vascular insufficiency, diabetes mellitus and an increased risk of lung, bladder and skin cancers.
Diagnosis
Obtaining a history of exposure to arsenic in a patient with correlating multi-system clinical findings is the best approach to diagnosing arsenic poisoning. Abdominal radiographs may reveal hyperlucencies in the gastrointestinal tract, however, radiographic findings may be negative in patients with significant exposures. The finding of elevated urinary arsenic concentrations is important in confirming arsenic poisoning (especially acute). Markedly elevated spot urine levels may be useful, to confirm a diagnosis in symptomatic patients; however 24-hours urine arsenic levels are more accurate and may remain elevated for longer periods of time after exposure. Because organic arsenic from ingested seafood and seaweed can elevate total urinary arsenic, samples should be speciated (to confirm inorganic vs. organic arsenic) or drawn after a one week period of abstinence from seafood or seaweed. Blood arsenic levels are highly variable and rarely beneficial. Hair arsenic testing is subject to external contamination, and variability in growth and uptake patterns, and is thus unreliable in diagnosing the type or level of exposure.
Treatment
Patients arriving at a health care facility after arsenic exposures require assertive management. While gastrointestinal decontamination is unlikely to be of benefit, whole-bowel irrigation with an iso-osmotic, isoelectric cathartic (eg. polyethylene glycol solution) can be considered if an abdominal radiograph suggests the presence of large quantities of arsenic in the gastrointestinal tract. Hypotension and fluid loss should be treated with aggressive intravenous hydration to maintain blood pressure and urinary output. Electrolytes and serum glucose levels should be monitored and corrected. When ventricular dysrhythmias are encountered following arsenic exposure, class IA, IC and III antidysrhythmics should be avoided. Chelation in acutely-ill patients should involve the intramuscular administration of dimercaprol (BAL) at 3-5 mg/kg every 4-6 hours. BAL should be avoided in patients with peanut allergies and those known to be G-6-PD deficient. Once patients are hemodynamically stable and have adequate gastrointestinal function, they can receive oral succimer (DMSA) at 10 mg/kg every 8 hours. Succimer can also be given for chronic arsenic poisoning. Chelation therapy is not indicated for organic arsenic found in the urine of asymptomatic patients. Other chelating agents, such as EDTA and penicillamine have not been shown to be beneficial in arsenic poisoning. Hemodialysis is largely ineffective in removing bound or unbound arsenic, and should be considered only in patients with poor renal function.
Summary and discussion of case questions
- The toxicity of arsenic involves the inhibition of cellular metabolism resulting in cardiovascular collapse and arrhythmias; induction of oxidative stress leading to cell damage and hematological dysfunction; and alteration in gene expression resulting in mutaqenesis and carcinogenesis.
- In acute poisonings, gastrointestinal symptoms predominate, followed by hemodynamic instability and multiple organ dysfunction. With chronic poisonings, skin manifestations and peripheral vascular dysfunction may occur. With long term arsenic exposure, there is an increased risk of lung, skin and bladder cancers.
- Aggressive hydration, correction of electrolytes and serum glucose abnormalities, and appropriate chelation therapy are the mainstays of treatment. Gastrointestinal decontamination and hemodialysis have limited roles in therapy.