eMedicine Specialties > Emergency Medicine > Warfare - Chemical, Biological, Radiological, Nuclear and Explosives

CBRNE - Arsenicals, Arsine

Author: Kermit D Huebner, MD, FACEP, Research Director, Carl R Darnall Army Medical Center
Coauthor(s): Ren M Kinoshita, DO, PGY-2 Resident Physician, Department of Emergency Medicine, Carl R Darnall Army Medical Center
Contributor Information and Disclosures

Updated: Jul 15, 2009

Introduction

Background

Arsine, the most toxic form of arsenic, has some properties that may make it useful as a chemical warfare (CW) agent; it is a colorless, odorless, nonirritating gas that is 2.5 times denser than air. At concentrations above 0.5 ppm, a garliclike odor may be noted; however, arsine is toxic at much lower concentrations. Arsine is often produced from the reduction of inorganic arsenic salts with the use of acids and metal cofactors such as zinc. Once in the body arsenic is readily distributed where peak serum levels occurs in approximately 60 minutes. The majority of arsenic is excreted by the kidneys, with some excretion in sweat, feces, and bile in small amounts.

Although it has been investigated as a CW agent, no battlefield use has been documented. During and prior to World War II, the British studied this agent and rejected its use in the field. They concluded that arsine was more than 10 times less toxic than phosgene (CG) and was both difficult to manufacture and highly flammable. Although arsine was determined not to be useful as a battlefield CW agent, concern exists that it may be useful as a small-scale weapon of assassination or terror.

In contrast, several arsine-derived organoarsenic compounds have been developed and used as CW agents, including lewisite (beta-chlorovinyldichloroarsine), adamsite (diphenylaminearsine), Clark I (diphenylchlorarsine), and Clark II (diphenylcyanoarsine).

Possible sources of occupational exposure are many, including microchip production in the semiconductor industry and other industries in which workers are involved in galvanizing, soldering, etching, and lead plating. It may also be produced inadvertently by mixing arsenic-containing insecticides and acids.

Pathophysiology

Inhaled arsine gas is distributed rapidly and causes massive red blood cell hemolysis that can potentially lead to global cellular hypoxia. The exact mechanisms leading to hemolysis have not been fully elucidated, but oxidative cell lysis has been suggested. 

A study of mice exposed to moderate-to-high levels of arsine for 90 days revealed a significant decrease in hemoglobin and hematocrit along with an increase in mean corpuscular hemoglobins and mean corpuscular hemoglobin concentrations after 5 days of exposure.¹  Blood collected at 15 and 90 days showed a less severe anemia but a greater increase in mean corpuscular volumes and absolute reticulocyte count indicating a regenerative response. At 90 days, the concentration of methemoglobin was increased along with an increase in intracellular denatured proteins, or Heinz bodies. In addition, this particular study determined that arsine gas significantly depletes reduced intracellular glutathione resulting in greater oxidative damage to red blood cells.  

Other mechanisms of hemolysis may include the inhibition of catalase and the formation of reactive oxidative species (ROS), such as hydrogen peroxide, within the cell. The damage induced by free radicals causes the denaturing of hemoglobin. This ultimately is believed to promote an abnormal association of hemoglobin with the erythrocyte membrane proteins that increase fragility of the erythrocyte membrane. Many researchers believe that hemolysis is a direct result of an arsenic dihydride intermediate and elemental arsenic produced from oxidized arsine. While there is disagreement of the reactive species involved and the mechanism of destruction, it is plausible that arsine causes cellular destruction by multiple mechanisms and the oxidative pathophysiology of arsine is well supported.    

To further support an oxidative mechanism, human blood exposed to arsine pretreated with a sulfahydryl inhibitor N-ethylmaleimide (NEM) in vitro, resulted in less hemolysis. These results suggest that arsine may negatively interact with membrane sulfahydrl groups resulting in ion membrane changes that ultimately lead to hemolysis.²

Interestingly, the oxidative cytotoxicity potential of arsenic has been used as treatment for certain malignant cancers. In treating malignant melanoma, a widely known oxidant named menadione was used in combination with arsenic to increase reactive oxidative species (ROS) production and subsequent apoptosis in tumor cells. The two were found to work synergistically with a significantly higher level of apoptosis in the group treated with arsenic.³  Similarly patients with acute promyelocytic leukemia (APL) were treated with transretinoic acid and arsenic trioxide. Compared to control, the group treated with the combination yielded a high complete remission rate of 93% and a significantly shorter time to enter complete remission.⁴  

In due course, with massive hemolysis, renal failure due to tubular destruction is an important sequelae of arsine toxicity.⁵  Although arsine may have direct effects on the renal system, most of the damage is believed to result indirectly from the breakdown of red blood cells and the increased load of hemoglobin. As in rhabdomyolysis, this destroys the tubular network leading to renal failure and is further complicated by renal hypoxia secondary to the decreased oxygen capacity of the blood.

Mortality/Morbidity

Arsine has been reported to cause immediate death at 150-250 ppm. In addition to absolute concentration, the duration of exposure is another factor that determines toxicity. Exposure to 25-50 ppm for 30 minutes or 100 ppm for less than 30 minutes may also result in massive red blood cell hemolysis and ultimately death. Symptoms may be noticed with concentrations as low as 0.15 ppm, and delirium may be seen at 10 ppm.

Most of the reported deaths are believed to have been secondary to acute renal failure. Of arsine-induced renal failure cases, 100% were fatal prior to the advent of hemodialysis. More recent mortality rates for patients with acute arsine toxicity report death in approximately 25% or less of reported cases.

Clinical

History

Most patients report little or no discomfort at the time of exposure. According to the Centers for Disease Control and Prevention (CDC), signs and symptoms generally occur 2-24 hours after exposure and are a result of massive hemolysis. Signs and symptoms include generalized weakness, dark urine, jaundice, and dyspnea. Oliguria and renal failure often occur 1-3 days after exposure. 

A case series documenting comprehensive descriptions of the symptoms and clinical course of arsine toxicity was published in 1975.⁶ Eight sailors were exposed to arsine gas that had escaped from a cylinder in the cargo hold of the Asiafreighter. Four sailors were exposed from 1 hour 5 minutes to 3 hours 45 minutes (cases 1-4). Four other sailors were exposed for approximately 15 minutes or less (cases 5-8).

All 8 sailors developed fever, headache, myalgia, epigastric pain, nausea, and vomiting between 1 and 12 hours of exposure. Cases 1-4 each developed intravascular hemolysis, renal failure, and marrow suppression with poor reticulocyte response and thrombocytopenia. Case 1 was exposed for the longest amount of time and suffered from anoxia and encephalopathy and was anuric for 5 weeks. Long-term complications for cases 1-4 included peripheral neuropathies, and case 1 was still severely disabled 6 months after the incident. Cases 5-8 developed much milder symptoms. All 8 sailors survived.

The CDC case definition of arsine poisoning includes the following:⁷

• Suspected: A case in which a potentially exposed person is being evaluated by health care worker or public health officials for poisoning by a particular chemical agent, but no specific credible threat exists. 
• Probable: A clinically compatible case in which a high index of suspicion (credible threat or patient history regarding location and time) exists for arsine exposure, or an epidemiologic link exists between this case and a laboratory-confirmed case. 
• Confirmed: A clinically compatible case in which laboratory tests have confirmed exposure.

The classic triad of symptoms in sublethal arsine exposures includes abdominal pain, hematuria, and jaundice. Symptoms by organ system are as follows:

• General - Fever, chills, shivering, thirst, malaise
• Cardiovascular - Long QT syndrome, hypovolemic shock, tachycardia, dysrhythmias
• Neurologic - Headache; dizziness; sensorimotor peripheral neuropathy (usually 1-3 wk after exposure); neuropsychological symptoms (several days after exposure) including memory loss, restlessness, and confusion
• Pulmonary - Dyspnea
• Gastrointestinal - Nausea, vomiting, abdominal pain, anorexia, jaundice
• Genitourinary - Red or dark-colored urine, flank pain, decreased urine output
• Muscle - Weakness, cramping

Physical

Physical signs and their severity depend on the concentration of arsine gas and the duration of the patient's exposure.

• Vital signs - Hyperthermia, tachypnea, tachycardia, hypotension
• Head, ears, eyes, nose, and throat (HEENT) - Discoloration of conjunctivae (red, orange, brown, or brassy; reportedly distinct from hyperbilirubinemia), scleral icterus, garlic odor to breath (possible)
• Pulmonary - Rales from acute respiratory distress syndrome (ARDS) in severe exposure
• Gastrointestinal - Abdominal tenderness, hepatomegaly
• Genitourinary - Costovertebral angle tenderness, colored urine (red, brown, or green from hemoglobinuria and/or methemoglobinuria)
• Extremities - Possible paresthesias and Mees lines with chronic arsenic toxicity from arsine exposure

Causes

• Arsine gas is used in the semiconductor industry when depositing arsenic on microchips. Exposure also may occur from producing, cleaning, or reclaiming gallium arsenide wafers.
• Arsine is released during the (usually accidental) production of hydrogen in an acid medium in contact with arsenic-contaminated metals.
• Arsine may potentially be used as a chemical warfare agent.
  • Suspect arsine exposure if multiple victims present in a delayed fashion with hematuria, abdominal or flank pain, and jaundice.
  • Severe acute arsine exposure may result in sudden death.

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