Arsenic Toxicity – 15 Interesting Facts
- Arsenic is a metalloid element that occurs naturally in the earth’s crust and exists in multiple forms: gaseous (arsine), organic, and inorganic (arsenite and arsenate)
- Toxic effects of arsenic depend largely on the degree and duration of exposure
- Acute toxicity is characterized by severe gastroenteritis, cardiovascular instability, seizures, acute respiratory distress syndrome, and renal failure
- Arsenic can affect nearly every major organ system and is also a well-known carcinogen
- In 2021, 714 arsenic exposures were reported to US poison centers3
- Arsenic exposure occurs through drinking water, food, agricultural and industrial applications, and herbal/medicinal preparations
- The diagnosis of acute or chronic arsenic poisoning is made primarily on the basis of history and clinical presentation in the setting of a possible exposure
- Acute exposure presents primarily with initial signs and symptoms of gastrointestinal distress; central and peripheral nervous system effects such as peripheral neuropathy and encephalopathy may also occur
- Chronic arsenic toxicity manifests initially with dermatologic changes such as hyperpigmentation and hyperkeratosis; cancer and multiorgan system dysfunction may arise secondary to long-term exposure
- 24-hour urine collection to assess for arsenic is the preferred diagnostic test to confirm diagnosis, however, a normal value does not exclude arsenic toxicity
- Adjunct studies such as abdominal radiographs, lumbar puncture, and ECG assist in the evaluation of arsenic toxicity
- Acute arsenic toxicity can be life threatening and necessitates aggressive supportive therapy
- Chelation therapy is the antidote to arsenic toxicity
- Patients who are acutely symptomatic should be admitted to a unit able to provide the appropriate level of care
- Although early chelation of acute arsenic toxicity has shown improved morbidity and mortality, neurologic injuries may be permanent
Alarm Signs and Symptoms
- Hemodynamic instability
- Encephalopathy
- Seizures
Introduction
- Arsenic is a metalloid element that occurs naturally in the earth’s crust and exists in multiple forms: gaseous (arsine), organic, and inorganic (arsenite and arsenate)
- The name arsenic, which is derived from the Greek word arsenikon, meaning potent, has become synonymous with poison
- Inorganic arsenate (pentavalent arsenic) and arsenite (trivalent arsenic) are the most toxic, while organoarsenical compounds (“fish arsenic”) are generally considered to have little toxicity
- Due to availability, low cost, and tasteless and odorless characteristics, arsenic is a common homicidal or suicidal agent
- It is also a possible agent of chemical warfare
- Arsenic Toxicity
- Toxic effects of arsenic depend largely on the degree and duration of exposure
- A single large exposure can produce rapid and even fatal effects
- A smaller chronic dose of arsenic leads to delayed or gradual effects that occur over months to years and can cause alterations in gene expression, signal transduction, and apoptosis and can cause chromosomal aberrations resulting in carcinogenesis
- Acute toxicity is characterized by severe gastroenteritis, cardiovascular instability, seizures, acute respiratory distress syndrome, and renal failure
- Arsenic can affect nearly every major organ system and is also a well-known carcinogen1
- Toxic effects of arsenic depend largely on the degree and duration of exposure
Epidemiology
- In 2006, arsenic exposures (including arsenic-based pesticides) represented 1361 of the over 2 million total poison exposures reported to the American Association of Poison Control Centers Toxic Exposure Surveillance System2
- Of these exposures, 377 were reported in children younger than 6 years of age.
- Of these 1361 exposures, one death was reported
- By 2021, the number of arsenic exposures reported to US poison centers had dropped to 714 (including arsenical pesticides) of the 2,080,917 total reported poison exposures, with 1 death3
- These 714 exposures included 35 children less than 5 years of age
- This dramatic decline was largely attributed to the to the cancellation by US EPA of 5 arsenical pesticides and dozens of arsenical herbicides in 20093
Etiology
- The major sources of environmental arsenic are drinking water and food
- Water coursing along geologic belts of arsenic can become highly contaminated causing polluted drinking water
- Seafood can contain large amounts of organic arsenic, a relatively nontoxic form
- Grains and meats are also sources of arsenic
- Arsenic is also used in various agricultural and industrial applications
- Used in various insecticides, herbicides, fungicides, and wood preservatives
- Used as a rat and ant poison
- Used in smelting/mining, glass making, metallurgy, semiconductor manufacturing
- Historically arsenic has been found in medicinal preparations as well
- Ayurvedic medications, herbals, Trisenox, opium, and cocaine may be purposely or inadvertently adulterated with arsenic
Diagnosis
Approach to Diagnosis
- The diagnosis of acute or chronic arsenic poisoning is made primarily on the basis of history and clinical presentation in the setting of a possible exposure
- Evaluate patient’s medical history to determine possible sources of exposure as well as symptom onset, duration, and evolution
- Ingestion is the usual pathway of toxicity; however, significant toxicity can also be seen following inhalation or dermal exposure
- Initial symptoms predominately manifest as gastrointestinal distress, but may also include peripheral paresthesias, primarily of the lower extremities
- Examination findings in acute toxicity may include hemodynamic instability, encephalopathy, and peripheral neuropathy; while chronic toxicity may be suggested by hyperpigmentation and hyperkeratosis
- The most useful test for confirming arsenic exposure is a 24-hour urine collection; however, this has limited immediate clinical utility as results are not immediately available
- In an emergency, a single urine void or “spot” urine may be collected as a substitute for a 24-hour collection
- Definitive diagnosis relies on finding a concentration of greater than 50 mcg/L arsenic, 100 mcg/g of creatinine, or a total of greater than 100 mcg arsenic in a 24-hour urine collection
- Abdominal radiograph may be useful in acute ingestion as inorganic arsenic is radiopaque
History
- Assess patient’s current symptoms and possible sources of exposure
- Exposure sources include:
- Home heating methods (burning of arsenic-treated wood in stoves or fireplaces)
- Drinking water source
- Dietary sources
- Location of residence in relation to agricultural or industrial activities
- Occupational (eg, agriculture, smelting, semiconductor manufacturing)
- Use of folk, herbal, or homeopathic remedies
- Acute toxicity
- Initial symptoms
- Gastrointestinal symptoms include oral irritation and burning in the oropharynx and esophagus, followed by nausea, vomiting, and severe diarrhea
- Diarrhea is similar to the “rice water” stools associated with cholera
- Hemorrhagic gastroenteritis and necrosis and perforation of the gastrointestinal tract may also occur
- CNS (central nervous system) symptoms may also occur
- Headache, confusion, encephalopathy and seizures
- Irritability, hallucinations, and delirium
- Gastrointestinal symptoms include oral irritation and burning in the oropharynx and esophagus, followed by nausea, vomiting, and severe diarrhea
- Days to weeks after acute ingestion, further symptoms may develop:
- Peripheral neuropathy may occur with paresthesias and absence of pain, touch, and temperature sensations in a stocking-glove distribution
- Motor weakness may develop and progress to flaccid paralysis
- Initial symptoms
- Chronic toxicity
- Arsenic can affect nearly every major organ system and is also a well-known carcinogen
- Dermatologic changes such as hyperpigmentation and hyperkeratosis (palmar and plantar) are among the first symptoms of chronic arsenic toxicity
- Sensorimotor peripheral neuropathy
- Gastrointestinal/hepatic injuries including cirrhosis and portal hypertension
- Hematopoietic system – leading to pancytopenia
- Chronic encephalopathy with headache and changes in cognition and personality
- Chronic exposure may also lead to chronic medical conditions such as hypertension, diabetes mellitus, ischemic heart disease, peripheral vascular disease and various cancers
- Arsenic can affect nearly every major organ system and is also a well-known carcinogen
- Exposure sources include:
Physical Examination
- Acute arsenic toxicity is characterized by:
- CNS
- Confusion, delirium, encephalopathy, seizure activity
- Peripheral nervous system
- Decreased sensation of pain, temperature, and touch
- Diminished deep tendon reflexes
- Motor weakness may occur and progress to ascending flaccid paralysis
- Cardiovascular
- Hypotension, dysrhythmia
- Gastrointestinal
- Nausea, vomiting
- Abdominal pain
- Findings of hepatitis including right upper quadrant pain, jaundice
- Pulmonary
- Cough, shortness of breath
- Crackles due to pulmonary edema
- Head, eyes, ears, nose, and throat
- Mucus membrane irritation
- Dermatologic
- Transverse lines across the finger and toenails (Mees’ lines) appear after 1 to 2 weeks and are characteristic of acute arsenic poisoning (do not appear after chronic exposure)
- Transverse lines in hair
- CNS
- Chronic arsenic toxicity is characterized by:
- CNS
- Encephalopathy, seizure activity
- Personality changes
- Psychosis
- Peripheral nervous system
- Decreased sensation and motor strength to peripheral nerves
- Cardiovascular
- Dysrhythmias
- Facial and peripheral edema due to increased vascular permeability and third-spacing
- Gastrointestinal
- Hepatoxicity including sequelae of cirrhosis (eg, jaundice, ascites) and portal hypertension
- Pulmonary
- Chronic cough
- Head, eyes, ears, nose, and throat
- Stomatitis
- Laryngitis
- Dermatologic
- Hypo or hyperpigmentation, hyperkeratosis of palms/soles are among the first symptoms of chronic arsenic toxicity
- Skin cancers (eg, Bowen’s disease (intraepithelial squamous cell carcinoma))
- Alopecia
- CNS
Laboratory Tests
- Utility of laboratory diagnostic studies depends on whether the exposure is acute, chronic, or remote, with residual clinical effects
- Most appropriate test for confirming excessive arsenic exposure is a 24-hour urine collection and analysis
- An elevated arsenic level confirms the diagnosis of arsenic exposure, but a normal level does not exclude the diagnosis
- Normal urine levels of arsenic in an unexposed person should be less than 25 mcg per 24 hours or 10 to 30 mcg/L of urine4
- Arsenic toxicity is diagnosed when greater than 100 mcg arsenic is found in a 24-hour urine collection
- Different types of arsenic have different toxicokinetic profiles5
- Urinary levels of inorganic arsenic, both trivalent and pentavalent, peak within 10 hours and normalize as soon as 20 to 30 hours after ingestion
- Levels of urinary methylarsonic acid and dimethyarsinic acid peak within 40 to 50 hours after ingestion and normalize approximately 6 to 20 days after ingestion
- In infants and children, a 6- to 8-hour timed urine specimen can be substituted for a full 24-hour collection
- An elevated arsenic level confirms the diagnosis of arsenic exposure, but a normal level does not exclude the diagnosis
- Consider use of a single urine void or “spot” as a substitute for a 24-hour collection when information is needed emergently
- This test measures arsenic per gram of creatinine and thus is unreliable in children due to variable creatinine excretion
- Acute toxicity has been reported with spot urine arsenic level ranging from 192,000 to 198,450 mcg/L6
- Because urinary excretion of arsenic is intermittent, definitive diagnosis relies on finding a concentration of greater than 50 mcg/L arsenic, 100 mcg/g of creatinine7
- Urinary arsenic excretion varies inversely with the postexposure time period, but low-level excretion may continue for months after exposure
- Falsely elevated results may occur
- Due to improper specimen collection
- Urine should be collected in metal-free containers
- Due to seafood consumption
- When seafood is ingested, urinary arsenic levels may transiently increase to 200 to 1700 mcg/L8
- Therefore, laboratory arsenic speciation into organic arsenobetaine (predominant arsenic in seafood) is needed to determine the actual type and source of the exposure
- If speciation is impractical, patients can abstain from fish consumption for a minimum of 1 week prior to testing
- Due to improper specimen collection
- Other arsenic tests
- Serum
- It will usually be elevated in a recent acute exposure, but is rapidly cleared after several hours
- Serum levels of arsenic in unexposed persons are less than 3 mcg/dL9
- Due to rapid clearance
- Findings are not reliable if there is a significant delay between ingestion and presentation
- Concentrations are often normal in cases of chronic toxicity
- Post-chelator challenge tests are not recommended
- Scientifically acceptable reference values have not been established
- Comparison of post-chelator values to normal reference values have not shown evidence of utility
- Serum
- General laboratory studies to evaluate for systemic toxicity
- A complete blood count with peripheral smear, seeking the presence of anemia, leukopenia, thrombocytopenia, and/or basophilic stippling
- A chemistry panel to assess renal insufficiency
- Liver function tests to assess elevated aminotransferases and bilirubin
- Urinalysis may show proteinuria, hematuria, and pyuria
- Pregnancy test as arsenic has shown adverse fetal effects
Imaging Studies
- Abdominal radiographs
- Arsenic is radiopaque, therefore an abdominal radiograph may demonstrate the material in the GI tract after an acute ingestion10
- The rapid absorption of arsenic may limit the usefulness of this test after several hours
Diagnostic Procedures
- Lumbar puncture
- Cerebrospinal fluid analysis in patients with CNS findings (including ascending flaccid paralysis) due to arsenic may be normal or exhibit mild protein elevation
- This allows differentiation from patients with Guillain-Barre syndrome, who typically have an elevated protein concentration after the first week of the illness
Diagnostic Tools
- ECG (electrocardiogram)11
- Prolongation of QT interval may occur
- Other findings may include cardiac dysrhythmias such as torsades de pointes, ventricular fibrillation, and bradycardia
Differential Diagnosis
Table 1. Differential Diagnosis: Arsenic toxicity.
| Condition | Description | Differentiated by |
|---|---|---|
| Gastroenteritis | Nausea, vomiting, diarrhea, and abdominal pain | Self-limited course with viral, bacterial, or other etiology |
| GBS (Guillain-Barre Syndrome ) | Autoimmune disorder causing ascending flaccid paralysis | Not associated with GI symptomsElevated cerebrospinal fluid protein found in GBS |
| Psychiatric disease | Mental illness that affects mood, thinking, and/or behavior | Onset of symptoms does not coincide with arsenic exposure |
| Sepsis | Syndrome characterized by body’s systemic response to infection | Associated with a viral or bacterial infectious agentResponds to appropriate antibacterial/antiviral therapy |
Treatment
Approach to Treatment
- Acute arsenic toxicity can be life threatening and necessitates aggressive supportive therapy
- Hypotension should be addressed with volume replacement as well as vasopressors and inotropes if needed
- Cardiac monitoring and management of dysrhythmias is required
- Discontinue any ongoing exposure
- Consider whole bowel irrigation or gastric lavage if radiopaque material is seen on radiograph
- Chelation therapy
- Chelation therapy should be administered immediately when acute arsenic poisoning is believed to be the most likely diagnosis, based on history and symptomatology
- Treatment of arsenic toxicity may include the use of chelating agents dimercaprol (British antilewisite or BAL), DMSA (dimercaptosuccinic acid) or DMPS (dimercaptopropanesulfonic acid)
- Hemodialysis is not effective for arsenic removal, but may be indicated for management of patients with renal failure
Nondrug and Supportive Care
- Acute arsenic toxicity can result in myocardial dysfunction, gastrointestinal fluid losses, and systemic vasodilation requiring significant intravascular fluid repletion1213
- Address hypotension and volume loss
- Replete volume with crystalloid fluids and consider blood products if GI hemorrhage is ongoing
- Exercise caution
- Note that due to increased vascular permeability, aggressive fluid repletion may lead to pulmonary and/or cerebral edema
- Consideration should be given to bedside ultrasound for assessment of fluid status14
- Consider invasive monitoring of central venous pressure and pulmonary arterial and wedge pressures in guiding the use of fluid administration as needed
- Address hypotension and volume loss
- All acutely-poisoned patients should be placed on a cardiac monitor and evaluated for cardiac dysrhythmias or conduction abnormalities
- Ventricular tachycardia and fibrillation can be treated with lidocaine and/or amiodarone, and defibrillation1115
- Torsades de pointes can be treated with isoproterenol, magnesium, and/or overdrive pacing
Drug Therapy
- Chelating agents are the antidotes for severe arsenic poisoning
- Initiate chelation therapy as soon as possible if acute arsenic toxicity is suspected
- Consider chelation for management of chronic arsenic poisoning
- May accelerate metal excretion and decrease concentration of arsenic in some tissues
- Therapeutic efficacy in reducing morbidity and mortality is not established16
- For cases of suspected chronic toxicity, therapy can wait until laboratory verification of the diagnosis is made unless the patient’s clinical status is deteriorating
- Three chelating agents are available in the United States, each with their own efficacy and safety profile
- Dimercaprol (British antilewisite or BAL)
- Standard therapy for acute inorganic toxicity
- BAL is a lipid-soluble dithiol chelator formulated in peanut oil
- Method of action:
- Binds to arsenic to form a BAL-thioarsenite compound that is readily eliminated by the kidneys
- Efficacy:
- Reduces mortality of acute toxicity if given early (i.e., within 6 hours of exposure)
- In one study of 15 patients with encephalopathy, all but one patient improved clinically within 24 hours of BAL initiation17
- Reports suggest prevention of neuropathy if BAL therapy is instituted within hours of ingestion; however it is not effective treating neuropathy several weeks after the acute exposure71819
- Because BAL is lipid soluble, it may be more efficacious than DMSA and DMPS (see below), both of which are water soluble, in removing arsenic from tissues20
- Dose:
- 3 to 5 mg/kg intramuscularly every 4 hours until the 24-hour urinary arsenic excretion is less than 50 mcg/L
- Potential adverse effects of BAL include:
- Tachycardia
- Elevated temperature and blood pressure
- Nausea
- Vomiting
- Headache
- Burning sensation of the lips
- Seizures
- DMSA, 2,3-dimercaptosuccinic acid
- DMSA is an oral analog of BAL and approved by the FDA for treatment of lead poisoning in children
- DMSA may be substituted for BAL once GI injury has resolved and gut motility has returned in acutely ill patients
- For patients with chronic toxicity, DMSA may be the treatment of choice if DMPS is not available
- Efficacy:
- Animal studies demonstrate that DMSA is equal or superior to BAL in urinary and fecal elimination of arsenic as well as decreasing concentration of arsenic in liver, kidneys, spleen, and brain2122
- DMSA has been used successfully to chelate arsenic in humans23
- The dimercaptan-arsenic complex is water soluble, resulting in significant excretion of arsenic
- Dose:
- The optimal dosing is for arsenic poisoning is unknown, and some clinicians follow the treatment guidelines established for lead (ie, 10 mg/kg/dose by mouth every 8 hours)
- More frequent dosing, 7.5 mg/kg/dose by mouth every 6 hours, has also been suggested
- If urinary concentrations of arsenic remain elevated, prolonged therapy may be necessary
- DMPS, or 2,3-dimercaptopropanol-sulfonic acid (Unithiol, Dimaval)
- DMPS is a water-soluble analog of BAL used in the treatment of mercury, arsenic, and lead poisoning
- Although not approved by the FDA, DMPS can be requested for emergency use through an Individual Patient Investigational New Drug Application.
- The first step in the process is to request a Letter of Authorization from the medical product developer, in this case Heyl, a German pharmaceutical company (Heyl-Berlin.de)
- Efficacy:
- Animal studies demonstrate that DMPS is equal to or better than DMSA and BAL in reducing toxic effects of arsenic.242526
- Has also been associated with a reduction in tissue levels of arsenic in experimental animals and increased excretion of arsenic in human studies2728
- One randomized clinical trial found that DMPS significantly improved clinical scores and urinary excretion of arsenic compared with placebo in 21 patients with chronic arsenicalism29
- An additional case report found that DMPS administration was associated with recovery from severe arsenic-induced peripheral neuropathy30
- Dose:
- DMPS can be administered by oral, intramuscular, or intravenous routes
- The intravenous route should be reserved for those patients with a compromised cardiovascular or GI (gastrointestinal) status (GI erosions) that would impair oral absorption
- For severe acute toxicity
- 3 to 5 mg/kg IV (maximum dose 250 mg) given every 4 hours by slow intravenous infusion over 20 minutes
- Once the patient has been stabilized, oral DMPS, 4 to 8 mg/kg by mouth every 6 to 8 hours, is administered
- DMPS can be administered by oral, intramuscular, or intravenous routes
- Potential adverse effects of DMPS include:
- Skin reactions (rash, urticaria)
- Mucous membrane reactions
- Elevated body temperature
- Rapid intravenous administration may be associated with vasodilatation and transient hypotension
- Increased copper and zinc excretion
- Although DMPS increases the urinary excretion of copper and zinc, this effect should not be clinically significant in patients without preexisting deficiency of these trace elements
- D-Penicillamine
- Oral monothiol chelator originally developed as a chelator for copper, but useful for other heavy metal poisonings
- It should be used only when BAL, DMPS, and DMSA are unavailable
- Efficacy
- It has been used as a chelating agent for arsenic poisoning, although little experimental evidence validates its efficacy3132
- Dose
- 25 mg/kg dose (maximum, 1 g/24 hr) by mouth every 6 hours until the urinary arsenic is less than 50 mcg/L/ 24 hours
- Potential adverse effects include:
- Rash
- Leukopenia
- Thrombocytopenia
- Nephrotoxicity
- Dimercaprol (British antilewisite or BAL)
Treatment Procedures
- Consider gastric lavage if radiopaque material is seen on abdominal radiograph
- Efficacy may be limited due to rapid absorption of arsenic
- Consider whole-bowel irrigation after gastric lavage to decontaminate the remainder of GI tract3334
- Continuous nasogastric suction may be used to remove arsenic re-secreted in gastric or biliary secretions35
- One study reported detectable arsenic in gastric aspirates of three patients 5 to 7 days following ingestion36
- Hemodialysis is not useful for removal of arsenic, but may be indicated for management of concurrent renal failure373839
Admission Criteria
- Admit patients who are acutely symptomatic for supportive care and consideration of chelation therapy
- Admit patients with encephalopathy or hemodynamic instability to an intensive care unit
- Note: if homicidal or suicidal intent is suspected for hospitalized patients, care should be taken to avoid any further exposure (eg, contaminated food, medicines)
Special Considerations
Pediatrics
- Children can be exposed to high concentrations of arsenic from contaminated surfaces or soil over their lifetime due to their normal hand-to-mouth activity, thus increasing their risk for cancer and chronic toxicity
- Concern has been expressed about the prevalence of arsenic in cereals and juices marketed for children in excess of the EPA’s 10 ppb limit for arsenic in water
- Excess arsenic has been identified in baby rice cereals, teething biscuits, and infant formulas40
- Children’s susceptibility to the toxic effects of arsenic may also be increased owing to differences in GI absorption; metabolism; higher body surface area, resulting in greater absorption per pound of body weight; higher respiratory rate; and different breathing zones
Pregnancy
- Arsenic exposure during pregnancy has been associated with fetal loss and infant death in pregnancy4142
- Administer chelation therapy to pregnant women who are clinically symptomatic from:
- Acute arsenic poisoning
- Chronic poisoning with documented exposure and elevated urine arsenic concentrations
Follow-up
Monitoring
- Long-term follow-up including physical therapy and rehabilitation may be necessary for patients with neurologic sequelae
Complications
- Known complications of arsenic toxicity include:
- Tracheal and bronchogenic carcinomas
- Hepatic angiosarcomas
- Intraepidermal carcinomas
- Squamous cell carcinomas
- Basal cell carcinomas43
- Myelogenous leukemia44
Prognosis
Prognosis of Arsenic Toxicity
The prognosis of arsenic poisoning depends on several key factors, including:
- Form of arsenic (inorganic vs. organic)
- Dose and duration of exposure (acute vs. chronic)
- Timeliness of treatment
- Age and baseline health of the individual
Acute Arsenic Toxicity
Prognosis: Variable to Poor
- High mortality if untreated: can lead to shock, multi-organ failure, and death within hours to days.
- If diagnosed early and treated promptly with chelating agents (e.g., dimercaprol/BAL), survival improves significantly.
- Neurologic and gastrointestinal damage may persist even after recovery.
Possible Long-Term Complications:
- Peripheral neuropathy
- Chronic fatigue
- Kidney/liver dysfunction
- Persistent gastrointestinal issues
Prognosis: Guarded to Poor (depends on exposure and management)
Chronic Arsenic Toxicity
- Often due to contaminated water or occupational exposure
- May lead to irreversible health effects over time
Common Long-Term Complications:
- Skin lesions: hyperpigmentation, keratosis
- Peripheral neuropathy
- Cardiovascular disease
- Diabetes
- Hematologic abnormalities
- Increased risk of cancers:
- Skin
- Bladder
- Lung
- Liver
Prognostic Factors (Worsen Outcome):
- Delayed diagnosis or treatment
- Inorganic arsenic exposure
- Renal or hepatic dysfunction
- Malnutrition or pre-existing conditions
- Continued exposure (especially in endemic areas)
Better Prognosis When:
- Exposure is identified early
- Chelation therapy is started promptly – Early chelation of acute arsenic toxicity has shown improved morbidity and mortality
- Patient is removed from the source
- Long-term monitoring and follow-up are maintained
- Neurologic injury may be permanent
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