ARSENIC PENTOXIDE

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

Specific Substances

1) Arsenic acid anhydride
2) Arsenic anhydride
3) Arsenic pentaoxide
4) Arsenic pentoxide, solid
5) Arsenic (v) oxide
6) Diarsenic pentoxide
7) Orthoarsenic acid

1.2.1) MOLECULAR FORMULA
1) As2-O5

Available Forms Sources

1) Arsenic pentoxide is an odorless, white crystalline amorphous solid pentavalent inorganic arsenic compound. It dissolves in water to form arsenic acid (AAR, 1987; Sax & Lewis, 1987; Sax & Lewis, 1989; Budavari, 1989; OHM/TADS , 1991; CHRIS , 1991; HSDB , 1991; EPA, 1985).

1) Arsenic pentoxide is used as an herbicide, wood preservative, metal adhesives, insecticides, fungicide, in dyeing and printing, and in the production of arsenates (National Institute for Occupational Safety and Health, 2008; Sax & Lewis, 1987; Budavari, 1989; OHM/TADS , 1991; HSDB , 1991; EPA, 1985).
2) Little is known about the effects of arsenic pentoxide aside from those of arsenic and other arsenical compounds in general. The following review is based on the toxic effects of arsenic and inorganic arsenic compounds, with effects attributed specifically to arsenic pentoxide noted.

Overview

Life Support

Clinical Effects

0.2.1)

A) USES: Arsenic pentoxide is an inorganic pentavalent arsenic compound. It is an odorless, white crystalline amorphous solid which dissolves in water, forming arsenic acid. Arsenic pentoxide is used as an herbicide, wood preservative, metal adhesives, insecticides, fungicide, in dyeing and printing, and in the production of arsenates. Little is known about the effects of arsenic pentoxide. The following review is based on the toxic effects of arsenic and inorganic arsenic compounds, with effects attributed specifically to arsenic pentoxide noted. Please refer to "ARSENIC" document for more information.
B) TOXICOLOGY: Pentavalent arsenic may be transformed to arsenic or substitute for inorganic phosphate in glycolysis, leading to uncoupling of oxidative phosphorylation and loss of ATP formation. Chronically, arsenic may cause DNA damage, mutation in the p-53 suppressor gene, and inhibition of DNA repair mechanisms leading to cancer. Arsenic-containing metals are considered non-toxic due to their low solubility.
C) EPIDEMIOLOGY: Toxicity from arsenic is uncommon and major effects are rare.
D) WITH POISONING/EXPOSURE

1) The following information is based on the toxic effects of arsenic and inorganic arsenic compounds.
2) ACUTE OVERDOSE: Arsenic pentoxide is readily absorbed into the body via ingestion, inhalation, and through mucosal membranes, and minimally absorbed through intact skin. Acute arsenic ingestion generally produces signs and symptoms within 30 minutes but symptoms may be delayed for several hours if ingested with food. Many arsenic compounds are severe irritants of the skin, eye, and mucous membranes; some may be corrosive. Contact produces local hyperemia, followed by vesicular or pustular eruptions. Acute inhalation exposures have resulted in irritation of the upper respiratory tract.
3) MILD TO MODERATE TOXICITY: Gastrointestinal symptoms occur rapidly after acute ingestion. Initial signs and symptoms include burning lips, throat constriction, cough, and dysphagia. Excruciating abdominal pain, severe nausea, vomiting, and profuse "rice water-like" diarrhea that may lead to hypovolemia follows these symptoms. In addition, hypovolemia from capillary leakage (third-spacing of fluids) is a common early effect. QTc prolongation may occur. Muscle cramps, facial edema, bronchitis, dyspnea, chest pain, dehydration, intense thirst, and fluid-electrolyte disturbances are also common following significant exposures. A garlic-like odor of the breath and feces may also develop. Subacute toxicity can produce neuropathies, both motor and sensory, and can progress to a Guillain-Barre like syndrome.
4) SEVERE TOXICITY: Hypotension and tachycardia are common early signs of severe poisoning. Hypotension may be resistant to fluid resuscitation and multi-organ failure may ensue. Fever and tachypnea may occur. These patients can develop ventricular dysrhythmias including torsade de pointes. Encephalopathy, seizures and coma have been reported. Acute renal failure, hemolytic anemia, rhabdomyolysis, and hepatitis may occur several days after ingestion.
5) CHRONIC TOXICITY: Inhalation is the most common route of exposure in arsenic workers. The sequence of chronic poisoning involves weakness, anorexia, hepatomegaly, jaundice, and gastrointestinal complaints, followed by conjunctivitis, irritation of the upper respiratory tract, hyperpigmentation, and eczematoid and allergic dermatitis. A hoarse voice and chronic upper respiratory septum is a common result after prolonged inhalation of white arsenic dust or fume. Peripheral nervous system symptoms may include numbness, burning, and tingling of the hands and feet; pain; paresthesias; tenderness; muscle fasciculations; gross tremors; ataxia; discoloration; and mental confusion. Muscular weakness, limb tenderness and difficulty walking may follow. The final phase consists of peripheral sensory neuropathy of the hands and feet. Associated motor neuropathy may occur as well. Certain arsenic compounds are known human carcinogens. Chronic exposure in either occupational settings or by drinking contaminated groundwater can cause poisoning and carries an increased risk of skin, lung, bladder, and possibly liver cancers.

a) ARSENIC PENTOXIDE: Chronic exposure to arsenic pentoxide was considered to be at least partly responsible for a complex pattern of health effects in one family including: sensory hypesthesias, muscle cramping, recurring pruritic conjunctivitis, otitis media, sinusitis, bronchitis, pneumonia, skin rashes described as "measle-like," reddened and thickened skin on the soles, malaise, decreased sensation in hands and feet, headaches, blackouts, grand mal seizures in the youngest children, epistaxis, easy bruising, alopecia, and premature labor.

0.2.3)

A) WITH POISONING/EXPOSURE

1) Patients may rapidly become hypotensive. Tachycardia may develop secondary to pain, hypovolemia, cardiac effects of arsenic or anxiety.

0.2.4)

A) WITH POISONING/EXPOSURE

1) Conjunctivitis, photophobia, dimness of vision, diplopia, and lacrimation may occur. A garlic-like odor may be detected on the breath. Recurrent episodes of otitis media and sinusitis were noted in a rural family chronically exposed to arsenic pentoxide from burning impregnated wood in a wood stove.

0.2.5)

A) WITH POISONING/EXPOSURE

1) Hypovolemic or hemorrhagic shock, torsades de pointes, ventricular fibrillation or tachycardia, QTc prolongation, and T-wave changes may be seen after acute ingestion. Myocarditis has been reported in chronic arsenic poisoning.

0.2.6)

A) WITH POISONING/EXPOSURE

1) Acute respiratory failure was seen in a patient with severe arsenic poisoning. Pulmonary edema may occur and be life-threatening. Adult respiratory distress syndrome (ARDS) has been reported.

0.2.7)

A) WITH POISONING/EXPOSURE

1) Toxic delirium and encephalopathy are possible complications. Peripheral neuropathy is common. Seizures may occur.

0.2.8)

A) WITH POISONING/EXPOSURE

1) Early symptoms within hours following arsenic ingestion include abdominal pain, vomiting, profuse bloody or watery ("rice-water-like") diarrhea, pain in the extremities and muscles, weakness, and flushing of the skin.

0.2.9)

A) WITH POISONING/EXPOSURE

1) Hepatocellular damage may occur, but is not common. A common postmortem finding is mitotic activity of hepatocytes.

0.2.10)

A) WITH POISONING/EXPOSURE

1) Anuria, hematuria, proteinuria, acute tubular necrosis, renal failure, and chronic renal insufficiency from cortical necrosis have been described.

0.2.12)

A) WITH POISONING/EXPOSURE

1) Electrolyte imbalances may occur.

0.2.13)

A) WITH POISONING/EXPOSURE

1) Hemolysis, pancytopenia, isolated leukopenia, or anemia may occur.

0.2.14)

A) WITH POISONING/EXPOSURE

1) Common skin findings may include flushing, diaphoresis, palmar hyperkeratosis, peripheral edema, hyperpigmentation, brawny desquamation, and exfoliative dermatitis. Transverse white striae of the nails may be seen. Shingles (Herpes Zoster) may also be a complication.

0.2.20)

A) Arsenic compounds have caused teratogenic and embryotoxic effects in the offspring of pregnant mice, rats, and hamsters. Fetotoxicity and fetal death are possible, but arsenic is NOT likely to be a significant risk to human reproduction at permissible occupational exposure limits.
B) Arsenic is excreted in the breast milk in both experimental animals and humans.
C) Systemic toxicity was present before any effects were noted on the testes. Arsenic pentoxide caused adverse parental effects when injected subcutaneously in mice and affected spermatogenesis when injected into the testes in rats.

0.2.21)

A) Arsenic pentoxide is considered to be a human carcinogen. An IARC review linked arsenic to skin cancer and a greater risk of lung cancer. OSHA has linked arsenic to cancer of the skin, lungs, lymph glands, and bone marrow. Bladder, kidney, prostate, liver, breast and colon cancer have also been linked with arsenic exposure.

0.2.22)

A) Malaise and easy bruising were noted in one case of arsenic pentoxide exposure.

Laboratory Monitoring

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Fluid resuscitation should be initiated immediately, but care must be taken to recognize pulmonary and cerebral edema when present. When a significant acute ingestion is confirmed, chelation therapy should be initiated immediately prior to laboratory confirmation. This will minimize time delay to treatment associated with prolonged laboratory result turn around. In chronic toxicity, the decision to chelate must be based upon patient condition and laboratory evaluation.

B) MANAGEMENT OF SEVERE TOXICITY

1) Aggressive life support measures should be instituted immediately. Anti-arrhythmic medications that prolong the QTc should be avoided. In severely ill patients, combined therapy with both BAL and an oral agent should be considered. If renal failure exists, the dose of BAL should be decreased after the loading dose.
2) INHALATION EXPOSURE: Inhalation is the most common exposure in arsenic workers. OSHA has set an "action level" of 5 mcg/m(3) of inorganic arsenic in the air over an 8-hour period. Initial treatment should be to remove the patient from the exposure and refer the patient to an occupational specialist for 24-hour urine collection. The decision to chelate will depend upon the patient's clinical status and urine arsenic concentration.
3) DERMAL EXPOSURE: Occasionally arsenic can cause a contact dermatitis or an exfoliative rash. Wash the area thoroughly and avoid further dermal contact. Topical steroid creams may decrease inflammation in these cases.
4) EYE EXPOSURE: Copious irrigation and ophthalmology follow-up.

C) DECONTAMINATION

1) PREHOSPITAL: Remove the contaminated clothing and wash the patient thoroughly.
2) HOSPITAL: Activated charcoal does not bind arsenic well. Gastric lavage and whole bowel irrigation should be considered for confirmed significant ingestions.

D) AIRWAY MANAGEMENT

1) Should be considered for patients with severe CNS depression at risk of aspiration.

E) ANTIDOTE

1) BAL and succimer are chelating agents used as antidotal therapy for arsenic toxicity. BAL: Symptomatic patients unable to tolerate oral medication should be treated with BAL 3 to 5 mg/kg/dose IM every 4 to 6 hours. The dose and frequency depend on the degree of toxicity seen. Higher doses of BAL invariably cause adverse effects. SUCCIMER: Should be used as soon as the patient is able to tolerate oral medication. DOSE: 10 mg/kg every 8 hours for 5 days, then decrease dosing to every 12 hours for 14 days. It may be more effective and causes fewer side effects than BAL. Chelation therapy should be stopped when the urinary arsenic level falls below 50 mcg per 24 hours.

F) VENTRICULAR DYSRHYTHMIAS

1) Institute continuous cardiac monitoring, obtain an ECG, and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders. Lidocaine and amiodarone are generally first-line agents for stable monomorphic ventricular tachycardia, particularly in patients with underlying impaired cardiac function. Because arsenic can cause torsades de pointes and QTc prolongation, amiodarone should only be used with extreme caution. Unstable rhythms require immediate cardioversion.

G) TORSADES DE POINTES

1) Treatment with magnesium; atrial overdrive pacing may also be necessary. Correct electrolyte abnormalities.

H) ENHANCED ELIMINATION

1) Arsenic is poorly dialyzable. Hemodialysis should only be considered for arsenic toxicity accompanied by renal failure.

I) PATIENT DISPOSITION

1) ADMISSION CRITERIA: All patients with acute arsenic toxicity should be admitted.
2) CONSULT CRITERIA: Consult a medical toxicologist and/or poison center for all potentially significant arsenic exposures.

J) PITFALLS

1) Failure to consider arsenic poisoning in patients with prolonged gastrointestinal illness and cardiac conduction abnormalities. Failure to remove fish or other arsenic sources from the diet prior to testing urine arsenic levels.

K) DIFFERENTIAL DIAGNOSIS

1) Infectious gastroenteritis may have a similar clinical presentation, though arsenic toxicity usually lasts longer and has more multi-organ system involvement. Toxic plant and mushroom ingestion may lead to a severe gastritis though most lack the systemic toxicity seen with arsenic. Theophylline overdose may have a similar presentation though diarrhea is not as predominant a feature as it is with arsenic poisoning.

0.4.3)

A) Inhalation is the most common exposure in arsenic workers. OSHA has set an "action level" of 5 mcg/m(3) of inorganic arsenic in the air over an 8-hour period. Initial treatment should be to remove the patient from the exposure and refer the patient to an occupational specialist for 24-hour urine collection. The decision to chelate will depend upon the patient's clinical status and urine arsenic concentration.

0.4.4)

A) Copious irrigation and ophthalmology follow-up.

0.4.5)

A) OVERVIEW

1) Occasionally arsenic can cause a contact dermatitis or an exfoliative rash. Wash the area thoroughly and avoid further dermal contact. Topical steroid creams may decrease inflammation in these cases.

Range Of Toxicity

Clinical Effects

Hepatic

3.9.1)

A) WITH POISONING/EXPOSURE

1) Hepatocellular damage may occur, but is not common. A common postmortem finding is mitotic activity of hepatocytes.

3.9.2)

A) LIVER DAMAGE

1) WITH POISONING/EXPOSURE

a) Hepatocellular injury may occur after severe acute arsenic poisoning but is not common (Lai et al, 2005; Donofrio et al, 1987b; ACGIH, 1991). Mitotic activity of hepatocytes may be a common postmortem finding of arsenic poisoning (Mackell et al, 1985).
b) Hepatomegaly was reported in 61 infants who ingested dried milk powder contaminated with arsenic (Dakeishi et al, 2006).
c) CHRONIC TOXICITY

1) Hepatocellular damage after chronic arsenic exposure may be more common than after acute; autopsy data from patients in India known to have liver disease demonstrated higher hepatic arsenic levels than controls (Narang, 1987a):

.	N	HEPATIC As
Controls (adults)	195	0.032 ppm
Cirrhosis	89	0.747 ppm
Fulminant Hepatitis	15	0.849 ppm
Indian Childhood Cirrhosis	39	0.865 ppm
Wilson's Disease	4	2.229 ppm

2) Liver biopsies from patients with hepatomegaly thought secondary to arsenic in well water in India showed various degrees of fibrosis and expansion of the portal zone resembling non-cirrhotic portal fibrosis (Mazumder et al, 1988; Guha Mazumder et al, 1992; Rahman et al, 2001).
3) NON-CIRRHOTIC PORTAL HYPERTENSION has been associated with chronic arsenic exposure (Guha Mazumda & Das Gupta, 1991; Nevens et al, 1990; Guha Mazumder et al, 1988; Duenas et al, 1998).

a) Portal hypertension has been noted with the use of Fowler's solution for 3 years (Tsuji et al, 2004).

Genitourinary

3.10.1)

A) WITH POISONING/EXPOSURE

1) Anuria, hematuria, proteinuria, acute tubular necrosis, renal failure, and chronic renal insufficiency from cortical necrosis have been described.

3.10.2)

A) ACUTE RENAL FAILURE SYNDROME

1) WITH POISONING/EXPOSURE

a) Oliguria, anuria, hematuria, proteinuria (National Institute for Occupational Safety and Health, 2008; Majid Cheraghali et al, 2007; Schoolmeester & White, 1980; Zaloga et al, 1970) , acute tubular necrosis, renal failure have occurred following acute arsenic exposure (Lai et al, 2005; Giberson et al, 1976; Vaziri et al, 1980; Moore et al, 1994a; Bartolome et al, 1999), and chronic renal insufficiency from cortical necrosis has been described (Gerhardt et al, 1978).
b) A prospective study, involving 100 arsenic-exposed subjects, showed an increased incidence in hematuria, urinary ketones, and urinary bilirubin in subjects exposed to arsenic concentration of 50 to 150 mcg/L as compared to those subjects exposed to arsenic concentrations less than 50 mcg/L. It is suggested that these urinary effect parameters may be useful as bio-markers of arsenic-induced renal injury, however further studies are warranted (Dalal et al, 2008).

B) IMPOTENCE

1) WITH POISONING/EXPOSURE

a) CHRONIC EXPOSURE: A study was conducted to determine the association between arsenic exposure and erectile dysfunction, and involved sending questionnaires to two groups of men. The first group consisted of 66 men who were at least 50-years-old and living in an arsenic-endemic area in Taiwan. The second group consisted of 111 men who were at least 50-years-old and living in a non-arsenic-endemic area. The questionnaire included standardized questions regarding demographics, lifestyle factors, and disease records, as well as an International Index of Erectile Function (ILEF-5) questionnaire used to measure the level of erectile function in each participant. The results of the study showed that the prevalence of erectile dysfunction (ED) was greater in the arsenic-endemic area (83.3%) as compared to the non-arsenic-endemic area (66.7%). The odds ratio (OR) in the greater than 50 ppb arsenic-exposed group was 3.4 (95% CI 1.1-10.3; p<0.05), indicating a significant risk of ED in those subjects as compared to those individuals with exposure to arsenic at a concentration of 50 ppb or less, and the risk of developing severe ED (ILEF</= 7) was also significantly higher in the greater than 50 ppb group with an OR of 7.5 (95% CI 1.8-30.9; p<0.05) after adjusting for free testosterone and other risk factors of ED (Hsieh et al, 2008).

Hematologic

3.13.1)

A) WITH POISONING/EXPOSURE

1) Hemolysis, pancytopenia, isolated leukopenia, or anemia may occur.

3.13.2)

A) HEMOLYSIS

1) WITH POISONING/EXPOSURE

a) Acute hemolysis may occur after acute arsenic poisoning (Kyle & Pease, 1965). It is usually Coomb's negative; abnormalities of developing normoblasts are also common (Ringenberg et al, 1988).

B) PANCYTOPENIA

1) WITH POISONING/EXPOSURE

a) Arsenic can disturb erythropoiesis and myelopoiesis (OSHA, 1988). After either acute or chronic arsenic exposure, pancytopenia may be seen (Rezuke et al, 1991; Kyle & Pease, 1965; Kjeldsberg & Ward, 1972; Bartolome et al, 1999). However, isolated anemia may also be seen.
b) The anemia is usually normochromic, normocytic, but may be hypochromic, microcytic (Kyle & Pease, 1965).
c) Basophilic stippling and rouleau formation of red cells may also be seen (Kyle & Pease, 1965; Harbison, 1998).

C) ANEMIA

1) WITH POISONING/EXPOSURE

a) ACUTE: Decreases in the hemoglobin and hematocrit values were the only sequelae possibly associated with an acute ingestion of approximately 1.2 grams arsenic as sodium arsenate in a 44-year-old woman(Chan & Matthews, 1990).
b) CHRONIC: Anemia has also been reported after chronic arsenic exposure (Guha Mazumder et al, 1992; Rahman et al, 2001).

D) MACROCYTOSIS

1) WITH POISONING/EXPOSURE

a) CASE REPORT/CHRONIC EXPOSURE: A patient presented with macrocytosis and peripheral neuropathy but without anemia after chronic exposure to an arsenical pesticide (Heaven et al, 1994).

E) DISSEMINATED INTRAVASCULAR COAGULATION

1) WITH POISONING/EXPOSURE

a) A 4-month-old developed evidence of disseminated intravascular coagulation within 11.5 hours of ingesting arsenic. He died 36 hours after ingestion despite aggressive chelation and resuscitation(Lai et al, 2005).

Summary Of Exposure

Vital Signs

3.3.1)

A) WITH POISONING/EXPOSURE

1) Patients may rapidly become hypotensive. Tachycardia may develop secondary to pain, hypovolemia, cardiac effects of arsenic or anxiety.

3.3.4)

A) WITH POISONING/EXPOSURE

1) HYPOTENSION: Patients may rapidly become hypotensive after acute arsenic poisoning from "third spacing" of fluids, diarrhea, or blood loss into the GI tract (Schoolmeester & White, 1980).

3.3.5)

A) WITH POISONING/EXPOSURE

1) TACHYCARDIA: Patients may become tachycardic secondary to pain, hypovolemia, cardiac effects of arsenic, or anxiety (Morgan, 1989).

Heent

3.4.1)

A) WITH POISONING/EXPOSURE

3.4.2)

A) WITH POISONING/EXPOSURE

1) ALOPECIA: Hair loss may occur with chronic arsenic exposure (Finkel, 1983; ITI, 1995).

a) Thinning of the hair and alopecia were noted in a rural family chronically exposed to arsenic pentoxide from burning impregnated wood in a wood stove (Peters et al, 1984).

3.4.3)

A) WITH POISONING/EXPOSURE

1) Conjunctivitis, photophobia, dimness of vision, diplopia, lacrimation, ulceration and sometimes hyperemia, chemosis, and conjunctival hemorrhage may occur (National Institute for Occupational Safety and Health, 2008; Grant, 1993; Heyman et al, 1956; Uede & Furukawa, 2003).
2) CONJUNCTIVITIS: Recurrent pruritic conjunctivitis was noted in a rural family chronically exposed to arsenic pentoxide from burning impregnated wood in a wood stove (Peters et al, 1984).

3.4.4)

A) WITH POISONING/EXPOSURE

1) OTITIS MEDIA - Recurrent episodes of otitis media and sinusitis were noted in a rural family chronically exposed to arsenic pentoxide from burning impregnated wood in a wood stove (Peters et al, 1984). The relationship to the arsenic exposure is unclear.

3.4.5)

A) WITH POISONING/EXPOSURE

1) BURNING: A sensation of burning, dryness and constriction of the oral and nasal cavities may occur (Finkel, 1983; Hathaway et al, 1996). Perforation of the nasal septum may result from irritation (Clayton & Clayton, 1994).
2) EPISTAXIS: Frequent nosebleeds were noted in a rural family chronically exposed to arsenic pentoxide from burning impregnated wood in a wood stove (Peters et al, 1984). The relationship to the arsenic exposure is unclear.

3.4.6)

A) WITH POISONING/EXPOSURE

1) BREATH: A garlic-like odor may be detected on the breath (National Institute for Occupational Safety and Health, 2008; Morgan, 1993; HSDB , 2000).

Cardiovascular

3.5.1)

A) WITH POISONING/EXPOSURE

3.5.2)

A) CONDUCTION DISORDER OF THE HEART

1) WITH POISONING/EXPOSURE

a) Ventricular tachycardia, ventricular bigeminy, and ventricular fibrillation have been described after acute arsenic ingestion (Lai et al, 2005; Peterson & Rumack, 1977; Goldsmith, 1980; St Petery et al, 1970; Brayer et al, 1997).

1) These dysrhythmias may be secondary to electrolyte imbalances rather than a direct toxic effect of arsenic on the myocardium (Sittig, 1985).

b) QRS morphology of the ventricular dysrhythmia is often consistent with torsades de pointes (Lai et al, 2005; Beckman et al, 1991; Goldsmith, 1980; St Petery et al, 1970).
c) Abrupt respiratory failure and asystole developed in a 21-year-old man who ingested 4 grams of arsenic (Moore et al, 1994a).

B) ELECTROCARDIOGRAM ABNORMAL

1) WITH POISONING/EXPOSURE

a) ECG changes have included QT prolongation, left axis deviations, peaked T waves, and also deeply inverted T waves (Lai et al, 2005; Gousios & Adelson, 1959; Heyman et al, 1956).
b) Abnormal ECG changes including ST elevation, flat T, and prolonged QT intervals were reported in infants following consumption of dried milk powder contaminated with arsenic. Analysis of a sample of milk powder estimated the arsenic concentration to be 4 to 7 mg/L (Dakeishi et al, 2006).

C) MYOCARDITIS

1) WITH POISONING/EXPOSURE

a) CHRONIC EXPOSURE: Interstitial myocarditis resulting in fatal ventricular arrhythmias has been reported after chronic exposure to arsenic (Hall & Harruff, 1989).

D) ISCHEMIA

1) WITH POISONING/EXPOSURE

a) CHRONIC EXPOSURE: A study of Taiwan residents who drank artesian well water containing high amounts of arsenic found chronic arsenic exposure to be related to ischemic heart disease in a dose-dependent manner. Mortality attributed to ischemic heart disease gradually declined over 17 to 20 years following cessation of consumption of the well water (Chang et al, 2004).

E) HYPOVOLEMIA

1) WITH POISONING/EXPOSURE

a) Hypovolemia from capillary leaking ("third spacing" of fluids) is a common early sign (National Institute for Occupational Safety and Health, 2008; Morgan, 1989; EPA, 1988; HSDB , 1991).

F) HYPOTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) Hypotension and tachycardia are common early signs (Shum et al, 1995; Schoolmeester & White, 1980).
b) Hypotension may develop after acute ingestion from gastrointestinal fluid loss or myocardial depression (Lai et al, 2005; Moore et al, 1994a).
c) CASE SERIES: Three patients, including a pregnant woman at 38 weeks gestation, developed hypotension (80 to 100/40 to 70 mmHg), respiratory distress, severe rash, blisters, oliguria, anuria, and leukopenia following dermal application, from neck to toe, of an isopropyl solution that contained 30% arsenic instead of the prescribed 25% benzyl benzoate for treatment of scabies. Despite intensive supportive therapy, all of the patients died, including the fetus, within 72 hours post-application (Majid Cheraghali et al, 2007).

G) HYPERTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) CHRONIC EXPOSURE: A dose-related increased incidence of hypertension was found in a Taiwanese population with chronic arsenic exposure in drinking water (Chen et al, 1995).
b) A cross-sectional analysis was conducted to evaluate the association between arsenic exposure from drinking water and blood pressure using baseline data of 10,910 participants in the Health Effects of Arsenic Longitudinal Study in Bangladesh (October 2000 to May 2002). Results suggested that the effect of low-level arsenic exposure on blood pressure is nonlinear and may be more pronounced in persons with lower intake of nutrients related to arsenic metabolism and cardiovascular health (Chen et al, 2007).
c) A cross-sectional study involving 8790 post-partum women who were exposed to arsenic in drinking water showed that as drinking water arsenic concentrations increased from 21 to 50, 51 to 100, and greater than 100 mcg/L, systolic blood pressure also increased by 1.88 mmHg (95% CI 1.03-2.73), 3.90 mmHg (95% CI 2.52-5.29), and 6.84 mmHg (95% CI 5.40-8.28), respectively. as compared to women in the control group (drinking water arsenic concentration of 20 mcg/L or less). Diastolic blood pressure also increased with increasing drinking water arsenic concentrations, with a change of 2.10 mmHg (95% CI 1.37-2.84), 2.72 mmHg (95%CI 1.53-3.92), and 3.17 mmHg (95% CI 1.92-4.41), respectively, as compared to women in the control group (Kwok et al, 2007).

H) MYOCARDIAL INFARCTION

1) WITH POISONING/EXPOSURE

a) A retrospective review of cases from 1950 to 2000, comparing patients from an arsenic-exposed region (region II) in Chile versus a non-arsenic-exposed region (region V) in Chile showed that the mortality rates from acute myocardial infarction (AMI) were significantly increased in region II during 1958 to 1970 (considered the peak exposure period, prior to installation of an arsenic removal plant), with a rate ratio (RR) in men of 1.48 (95%CI 1.37-1.59; p<0.001) and a RR in women of 1.26 (95% CI 1.14-1.40; p<0.001). From 1971 to 2000, the RR gradually decreased to a final recorded RR in men of 1.21 (95%CI 1-1.47; p=0.05) and a RR in women of 0.90 (95% CI 0.71-1.14 ; p=0.37). The RR for AMI, comparing region II and region V, varied according to gender and age. Within the peak exposure period of 1958-1970, the RR was the greatest in men and women at ages 30 to 39 years, at 2.27 (95% CI 1.61-3.20; p<0.001) and 2.51 (95%CI 1.43-4.42; p<0.01), respectively. In comparison with lung and bladder cancer (two prevalent cancers following arsenic exposure), excess deaths due to AMI were greater during the peak exposure period (1958-1970) with 452 and 129 deaths in men and women, respectively, as compared to 71 deaths in men (19 in women) and 17 deaths in men (10 in women) with lung and bladder cancer, respectively (Yuan et al, 2007).

Respiratory

3.6.1)

A) WITH POISONING/EXPOSURE

1) Acute respiratory failure was seen in a patient with severe arsenic poisoning. Pulmonary edema may occur and be life-threatening. Adult respiratory distress syndrome (ARDS) has been reported.

3.6.2)

A) COUGH

1) WITH POISONING/EXPOSURE

a) Patients may develop cough immediately after exposure to arsenic pentoxide (National Institute for Occupational Safety and Health, 2008).

B) APNEA

1) WITH POISONING/EXPOSURE

a) Acute respiratory failure presumably from severe weakness of respiratory muscles was reported in a patient with severe arsenic poisoning. The problem progressed despite dimercaprol therapy and required ventilatory assistance for one month (Greenberg et al, 1979).
b) Breathlessness was associated with asymmetric bilateral phrenic nerve involvement secondary to arsenic poisoning from contaminated opium in a 35-year-old opium addict (Bansal et al, 1991).
c) Abrupt respiratory failure and asystole developed in a 21-year-old man who ingested 4 grams of arsenic (Moore et al, 1994a).

C) ACUTE LUNG INJURY

1) WITH POISONING/EXPOSURE

a) Pulmonary edema, either noncardiogenic from capillary leaking, or cardiogenic from myocardial depression, may occur and be life-threatening (National Institute for Occupational Safety and Health, 2008; Morgan, 1989).

D) ADULT RESPIRATORY DISTRESS SYNDROME

1) WITH POISONING/EXPOSURE

a) Adult respiratory distress syndrome (ARDS) has been reported (Zaloga et al, 1970; Schoolmeester & White, 1980).

Neurologic

3.7.1)

A) WITH POISONING/EXPOSURE

1) Toxic delirium and encephalopathy are possible complications. Peripheral neuropathy is common. Seizures may occur.

3.7.2)

A) TOXIC ENCEPHALOPATHY

1) WITH POISONING/EXPOSURE

a) Toxic delirium and encephalopathy are complications of significant acute (National Institute for Occupational Safety and Health, 2008; Duenas-Laita et al, 2005; Jenkins, 1966; Quatrehomme et al, 1992) and chronic (Freeman & Couch, 1978; Morton & Caron, 1989) arsenic poisoning. The encephalopathy may be permanent and result in cortical atrophy one to six months after exposure (Fincher & Koerker, 1987).
b) PREVENTION: Early institution of chelation therapy may not be successful in preventing arsenic encephalopathy (Fincher & Koerker, 1987). However, BAL has been reported to reverse the encephalopathy seen after chronic arsenic exposure (Freeman & Couch, 1978; Beckett et al, 1986).

B) NEUROPATHY

1) WITH THERAPEUTIC USE

a) CASE REPORT: A toxic polyneuropathy resulting in quadriparesis has been reported within 2 weeks of beginning use of an arsenic-containing homeopathic preparation (Chakraborti et al, 2003).

2) WITH POISONING/EXPOSURE

a) ONSET: Peripheral neuropathy is common after either acute or chronic arsenic poisoning (Guha Mazumder et al, 1992; Nazmul Ahasan HAM, 2001; Tsuji et al, 2004; Duenas-Laita et al, 2005; Mukherjee et al, 2005). After acute exposure it usually begins one to 3 weeks later (Le Quesne & McLeod, 1977; Heyman et al, 1956; Goebel et al, 1990; Hahn et al, 2000).
b) INITIAL SIGNS: It usually begins as paresthesias of the soles of the feet, then the hands, progressing proximally over the next few days (Heyman et al, 1956). Severe muscle weakness and wasting then develops, causing severe disability (Le Quesne & McLeod, 1977; OSHA, 1988). In one case of arsenic poisoning from burning pressure-treated wood, symptoms were limited to bilateral pain and tingling of the feet along with difficulty sleeping and walking secondary to the pain in an 11-year-old boy (Hahn et al, 2000).
c) DIFFERENTIAL: The syndrome may initially be confused with Guillain-Barre (Donofrio et al, 1987b; Gherardi et al, 1990). Facial nerves are commonly involved in Guillain-Barre and almost never affected in arsenic poisoning (Jenkins, 1966).
d) PAIN: The paresthesias may be painful and are frequently described as severe burning pain in a stocking and glove distribution.
e) PHYSICAL FINDINGS of arsenic neuropathy usually include prominently decreased sensation to touch, pinprick, and temperature, frequently in a stocking and glove distribution (Heyman et al, 1956; Kelafant et al, 1993); loss of vibration sense is also common; profound muscle weakness and wasting, distal more so than proximal, is also seen (Donofrio et al, 1987b; Heyman et al, 1956; Hahn et al, 2000); wrist drop, foot drop, and fasciculations may be seen (Heyman et al, 1956).

1) GAIT may be altered by toxicity resulting in high-stepping, ataxic, waddling, or hesitation due to hyperpathia following chronic exposure (Rahman et al, 2001).

f) ELECTRODIAGNOSTIC STUDIES of arsenic neuropathy have shown a reduction of motor conduction velocity and marked abnormalities of sensory nerve action potentials (Le Quesne & McLeod, 1977).

1) Oh (1991) studied 13 victims of arsenic toxicity with peripheral neuropathy(Oh, 1991). Sensory and mixed nerve conduction was abnormal in all cases. Twelve of 13 had absent sural nerve potentials; 11 of 13 had absent median and ulnar nerve potentials. One of the cases reported suffered a steady worsening of nerve conduction until, 6 weeks later, no motor or sensory response could be found in any of the tested nerves.
2) CHRONIC EXPOSURE: A study, involving adolescents who were chronically exposed to arsenic via contaminated drinking water, demonstrated that cumulative arsenic exposure of greater than 100 mg resulted in a significant decrease in the nerve conduction velocity (NCV) of the sural sensory action potential (SAP). The authors speculate that slow NCV of sural SAP may be an early marker for the development of peripheral neuropathy associated with chronic arsenic exposure (Tseng et al, 2006).
3) A study of 43 arsenic exposed smelter workers found a negative correlation between estimated cumulative arsenic exposure and nerve conduction velocity (NCV) (Lagerkvist & Zetterlund, 1994). Seven workers had NCVs below the normal range. Workers were not assessed clinically for evidence of neuropathy.

g) NERVE BIOPSY may demonstrate various stages of axonal degeneration without demyelination (Le Quesne & McLeod, 1977) or with demyelination (Donofrio et al, 1987b).
h) DIMERCAPROL (BAL) does not seem to reverse arsenic neuropathy (Donofrio et al, 1987b; Heyman et al, 1956; Le Quesne & McLeod, 1977); recovery is usually very slow and incomplete. It has been claimed that if BAL is administered within hours of ingestion, however, that neuropathy may be prevented (Jenkins, 1966), although this is not true for all cases (Marcus, 1987).
i) CASE REPORT: A 35-year-old man with acute arsenic neuropathy with asymmetric bilateral phrenic nerve involvement made a significant recovery with D-penicillamine (250 mg three times daily) therapy (Bansal et al, 1991).
j) CASE REPORT: A patient with chronic exposure to an arsenical pesticide presented with peripheral neuropathy and macrocytosis, but without anemia (Heaven et al, 1994).
k) CASE REPORT: A 39-year-old woman developed progressive weakness and peripheral neuropathy leading to quadriplegia and requiring mechanical ventilation following an unknown type of exposure to arsenic. Analysis of her serum and urine revealed elevated arsenic (As) concentrations (290 mcg As/kg [normal <2 mcg/kg] and 2000 mcg As/L [normal <10 mcg/L], respectively). The patient slowly improved clinically following chelating therapy with DMSA; however, 5 years following intoxication, the patient continued to have residual paresthesias and weakness in her hands and distal lower extremities (Stenehjem et al, 2007).
l) CASE SERIES: In a large survey of arsenic poisoning from various water supplies in India, 37.3% (n=154 cases, total 413 subjects) of individuals developed clinical neuropathies. Of those cases, 80.5% (n=124 cases) had a sensory neuropathy and 30 cases had a motor component (Rahman et al, 2001).
m) CASE SERIES: In a study of 137 subjects chronically exposed to arsenic in drinking water, arsenic exposure was associated with elevated toe vibration threshold. Urinary arsenic and cumulative arsenic index were both significantly associated with elevated toe vibration threshold (Hafeman et al, 2005).
n) CASE REPORTS: Numbness in all four extremities were reported in three patients (a 45-year-old woman, her 23-year-old son, and a 5-year-old child) following dermal application, from neck to toe, of an isopropyl alcohol solution containing 30% arsenic instead of the prescribed 25% benzyl benzoate for treatment of scabies. The patients also experienced vomiting, pruritus, and blistering of the skin. With symptomatic and supportive therapy, all of the patients recovered and were discharged within 5 days post-admission; however, numbness of the extremities continued to persist (Majid Cheraghali et al, 2007).

C) SEIZURE

1) WITH POISONING/EXPOSURE

a) Seizures may occur (National Institute for Occupational Safety and Health, 2008; Hathaway et al, 1996; Harbison, 1998).

Gastrointestinal

3.8.1)

A) WITH POISONING/EXPOSURE

3.8.2)

A) GASTROENTERITIS

1) WITH POISONING/EXPOSURE

a) Early symptoms within hours following significant exposure to arsenic include thirst, abdominal pain, nausea, vomiting, profuse bloody or watery diarrhea (sometimes described as "rice-water like") (National Institute for Occupational Safety and Health, 2008; Majid Cheraghali et al, 2007; Lai et al, 2005; Gilman et al, 1985; Quatrehomme et al, 1992; Moore et al, 1994a; Brayer et al, 1997; Bartolome et al, 1999; Tsuji et al, 2004), pain in the extremities and muscles, weakness, and flushing of the skin. A sensation of burning and dryness of the oral and nasal cavities may occur.
b) Stool or emesis may have a garlic like odor (Lee et al, 1995).
c) Hematemesis may develop with severe poisoning(Lai et al, 2005).

B) GARLIC TASTE

1) WITH POISONING/EXPOSURE

a) A garlic or metallic taste may occur immediately after exposure to arsenic pentoxide (National Institute for Occupational Safety and Health, 2008).

Dermatologic

3.14.1)

A) WITH POISONING/EXPOSURE

3.14.2)

A) GENERALIZED EXFOLIATIVE DERMATITIS

1) WITH POISONING/EXPOSURE

a) Skin findings after either acute or chronic arsenic poisoning may include flushing, diaphoresis, diffuse pigmentation, hyperkeratosis of palms and/or soles, peripheral edema, hyperpigmentation, hypopigmentation, leuko-melanoderma, brawny desquamation, and exfoliative dermatitis (Heyman et al, 1956; Zaloga et al, 1970; Schoolmeester & White, 1980; Hutton & Christians, 1983; Huang et al, 1998; Ahasan, 2001; Tsuji et al, 2004; Dakeishi et al, 2006).
b) ENDEMIC ARSENISM: Outbreaks of arsenic poisoning from water are common in the West Bengal and Bangladesh countries, it was found that clinical symptoms often did not manifest until 6 months to 10 years after exposure. The first signs and symptoms of chronic exposure were related to dermatologic changes. Arsenical skin lesions included the following: melanokeratosis, diffuse melanosis, spotted melanosis (raindrop pigmentation), leucomelanosis and keratosis. Minor dermatological changes included: buccal mucous membrane pigmentation, nonpitting edema, and red eyes (without signs or symptoms of inflammation) (Mukherjee et al, 2005; Rahman et al, 2001).
c) INCIDENCE: In a review of 648 cases of patients with cutaneous lesions, 17 (2.6%) had cutaneous lesions associated with long-term arsenic exposure. Of those patients, 15 patients (88%) had asthma, of whom 14 (93%) ingested Chinese proprietary medicines which contained inorganic arsenic and the remaining patients had a history of ingesting well water contaminated with arsenic (Wong et al, 1998).

1) Bowen's disease (precancerous dermatosis) and palmar arsenical keratoses were reported in all 17 patients, 14 (82%) had plantar arsenical keratoses, four (24%) had arsenical keratoses on the arms, and four (24%) had arsenical keratoses at other sites. Eleven patients had macular hypopigmentation; no patient developed hyperpigmentation.

d) CASE REPORT: A 54-year-old woman presented with worsening alopecia and memory loss. She also experienced diarrhea, nausea, vomiting, fatigue, an erythematous rash bilaterally on her lower extremities, and onycholysis. A spot urine sample indicated an arsenic concentration of 83.6 mcg/g creatinine (normal <50 mcg/g creatinine). A review of the patient's medication history revealed that she had been taking kelp supplements for treatment of menopause (2 to 4 tablets/day for 1 year). Analysis of a kelp supplement sample showed an arsenic concentration of 8.5 mg/kg. Discontinuation of the supplements resulted in complete resolution of her symptoms. A repeat spot urine sample, obtained 2 months after the first urine sample, revealed an arsenic level of 25 mcg/L (normal 0-50 mcg/L) (Amster et al, 2007).
e) CASE REPORT: A 73-year-old man, from Thailand, presented with several dermal lesions, including basal cell carcinoma at the lower abdomen, arsenical keratoses on his left forearm and knee, and punctate palmoplantar keratosis. Analysis of his pubic hair and nails revealed elevated arsenic concentrations of 4.76 and 3.29 mcg/g, respectively (normal <3 mcg/g). The lesions resolved following treatment with 5% imiquimod cream. A review of the patient's history revealed that he had long-term exposure to Thai proprietary medicines, presumably containing arsenic (Boonchai, 2006).

B) CONTACT DERMATITIS

1) WITH POISONING/EXPOSURE

a) SENSITIZATION: Arsenic pentoxide can cause contact dermatitis (OSHA, 1988).
b) CASE REPORT: The organic arsenical pesticide cacodylic acid has caused airborne contact dermatitis (Bourrain et al, 1998).

C) MEE'S LINE

1) WITH POISONING/EXPOSURE

a) Transverse white striae of the nails (Mees' lines) may be seen after acute or chronic exposure (Duenas-Laita et al, 2005; Sass et al, 1993). Mees' lines commonly take 5 weeks to appear above the cuticle and advance 1 mm per week afterwards, allowing the approximation of the time of acute exposure (Heyman et al, 1956).

D) HERPES ZOSTER

1) WITH POISONING/EXPOSURE

a) Shingles have been reported following arsenic poisoning (Jenkins, 1966).

Musculoskeletal

3.15.2)

A) RHABDOMYOLYSIS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Mild rhabdomyolysis (CPK 1200 U/Liter) developed in a 21-year-old man who ingested 4 grams of arsenic (Moore et al, 1994a).

B) MUSCLE PAIN

1) WITH POISONING/EXPOSURE

a) CHRONIC TOXICITY: Myalgia and myopathy have been reported following chronic exposure, and are considered rare events (Rahman et al, 2001).

Endocrine

3.16.2)

A) HYPERGLYCEMIA

1) WITH POISONING/EXPOSURE

a) A 4-month-old infant developed hyperglycemia (serum glucose 286 mg/dL 6 hours after ingestion) after a lethal arsenic ingestion(Lai et al, 2005).

Reproductive

3.20.1)

3.20.2)

A) HUMANS

1) Arsenic is NOT likely to be a significant risk to human reproduction at permissible occupational exposure limits (Council on Scientific Affairs, 1985).
2) While arsenic is likely fetotoxic in humans, data are currently inadequate to determine whether or not such effects could occur in the absence of maternal toxicity (Council on Scientific Affairs, 1985).

B) ANIMAL STUDIES

1) Arsenic compounds have caused teratogenic and embryotoxic effects in the offspring of pregnant mice, rats, and hamsters when administered orally or parenterally ((RTECS, 2000); Schardein, 1993; Council on Scientific Affairs, 1985; Hood, 1972; Baxley et al, 1981). In some hamster experiments, no teratogenic effects were noted (Schardein, 1993; Hood & Harrison, 1982).
2) In a cultured mouse embryo system, sodium arsenate and arsenite were both teratogenic, resulting in abnormalities of cranial closure, abnormalities of the eye and optic nerve, and pharyngeal arch defects. The ED50 for arsenate was about threefold higher than than for arsenite (Tabocova et al, 1996).

3.20.3)

A) PLACENTAL BARRIER

1) NEONATAL DEATH - Acute ingestion of arsenic in a female with a 30 week pregnancy has been reported to result in the death of the infant born 4 days after the poisoning (Lugo et al, 1969). The child apparently died of hyaline membrane disease, but did have elevated tissue levels of arsenic. It seems apparent that arsenic can cross the placenta.
2) In studies of a population in Argentina exposed to environmental arsenic (drinking water arsenic approximately 200 mcg/L), cord blood concentrations (median 9 mcg/L) were almost as high as maternal blood concentrations (median 11 mcg/L).

a) Essentially all of the blood arsenic and about 90 percent of the urinary arsenic in both mothers and newborns was in the form of dimethylarsinic acid in comparison to 70 percent in the urine of non-pregnant women, suggesting that the methylation of arsenic may be up-regulated during pregnancy (Concha et al, 1998).

B) ENCEPHALOPATHY

1) Six women developing arsenical encephalopathy during the fourth to eighth months of pregnancy delivered normal children (Schardein, 1993).

C) EPIDEMIOLOGICAL STUDIES

1) Increased rates of spontaneous abortions and decreased birth weights in the offspring were found in a study of women living near a smelter in Sweden which emitted lead, sulfur dioxide, and arsenic. There was no increased incidence of congenital malformations in this group (Schardein, 1993). The significance of this study to pure chronic arsenic exposure during pregnancy is unclear.

D) FETOTOXICITY

1) AMA COUNCIL ON SCIENTIFIC AFFAIRS - Although arsenic compounds are likely fetotoxic in humans, exposure at permissible occupational levels is not likely to present a significant risk to human reproduction (Council on Scientific Affairs, 1985).

E) PLACENTAL DISORDER

1) A premature birth due to abruptio placenta or placenta previa occurred in the mother of a rural family who were chronically exposed to arsenic pentoxide from burning impregnated wood in a wood stove (Peters et al, 1984). The relationship to the arsenic exposure is unclear.

F) ANIMAL STUDIES

1) FERTILITY - Continuous dietary administration of up to 215 mg/kg of arsenic did not have adverse effects on fertility in female rats (Barlow & Sullivan, 1982).

3.20.4)

A) BREAST MILK

1) Arsenic is excreted in the breast milk in both experimental animals and humans (Barlow & Sullivan, 1982).

Carcinogenicity

3.21.1)

A) IARC Carcinogenicity Ratings for CAS1303-28-2 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) IARC Classification

a) Listed as: Arsenic pentoxide
b) Carcinogen Rating: 1

1) The agent (mixture) is carcinogenic to humans. The exposure circumstance entails exposures that are carcinogenic to humans. This category is used when there is sufficient evidence of carcinogenicity in humans. Exceptionally, an agent (mixture) may be placed in this category when evidence of carcinogenicity in humans is less than sufficient but there is sufficient evidence of carcinogenicity in experimental animals and strong evidence in exposed humans that the agent (mixture) acts through a relevant mechanism of carcinogenicity.

3.21.2)

3.21.3)

A) CARCINOMA

1) IARC REVIEW - An IARC review found that there is a causal relationship between medicinal, drinking water, or occupational heavy arsenic exposure and skin cancer. There is also a clearly increased risk of lung cancer in workers inhaling high levels of arsenic trioxide (IARC, 1987).
2) Arsenic pentoxide is considered to be a human carcinogen (Lewis, 1996).
3) IARC CANCER REVIEW - Sufficient Evidence in Humans ((RTECS, 2000))
4) The Occupational Safety and Health Administration (OSHA) has linked arsenic to cancer of the skin, lungs, lymph glands, and bone marrow (Anon, 1979). The EPA has classified inorganic arsenical compounds as Class A carcinogens based on sufficient human epidemiological evidence (EPA, 1988). The carcinogenicity of arsenic compounds has been reviewed (Berlin et al, 1991).
5) A study of a population in Taiwan drinking high-arsenic concentration artesian well water found a dose-response relationship between the amount of arsenic in the water and the incidence of mortality from bladder, kidney, skin, prostate, lung, and liver cancer (Chen et al, 1988).
6) Additional environmental exposure studies in various regions where arsenic exposure is endemic, recent eipdemiologic studies have suggested possible relationships of arsenic exposure to cancers of the lung (Hopenhayn-Rich et al, 1998; Smith et al, 1998), kidney (Hopenhayn-Rich et al, 1998), and bladder (Smith et al, 1998; Hopenhayn-Rich et al, 1996).
7) Arsenic has been linked to cancers of the skin and, possibly, to bronchogenic cancer (Wagner et al, 1979; ACGIH, 1986) IARC, 1973; (HSDB , 1991). Preneoplastic lesions due to sodium arsenite exposure have been found in human respiratory epithelium (Dong et al, 1995).

B) SKIN CARCINOMA

1) Basal cell and squamous cell carcinomas of the skin have been described after both acute (Renwick et al, 1981) and chronic (Jackson & Grainge, 1975; Wagner et al, 1979) arsenic exposure.
2) Two patients with arsenic-induced basal cell carcinomas of the skin also developed malignancies of other organs (breast and colon) (Jackson & Grainge, 1975).

C) HEPATIC CARCINOMA

1) One worker who was exposed to arsenious oxide and sodium arsenite for 20 years developed cirrhosis of the liver and primary liver carcinoma (Finkel, 1983).

Genotoxicity

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Testing must be correlated with the time of exposure and care must be taken to eliminate possible confounding factors such as food-derived arsenic (fish) or accumulated arsenic in those with chronic renal failure.
B) Diagnosis is based on elevated urinary arsenic levels. A spot urine may be done as a screen prior to chelation but arsenic excretion is intermittent, therefore a 24-hour urine arsenic collection is necessary for definitive diagnosis. A 24-hour urinary arsenic collection exceeding 100 mcg is usually abnormal, even after chelation.
C) Monitor CBC, serum electrolytes, liver enzymes, renal function tests, and a blood arsenic concentration in symptomatic patients.
D) Serial ECGs should be obtained to follow the QTc interval and continuous cardiac monitoring should be instituted in symptomatic patients.
E) Most arsenic compounds are radio-opaque, therefore abdominal X-rays may confirm acute ingestions and guide decontamination.

4.1.2)

A) ACUTE TOXICITY

1) A blood level of arsenic less than 7 mcg/100 mL (70 mcg/L) is considered in the normal range. Blood levels are highly variable and may be useful only after acute exposure to confirm diagnosis (Fesmire et al, 1988).
2) HEMODIALYSIS PATIENTS: were found to have highly elevated arsenic levels in serum and packed cells compared with age-matched historical controls: mean levels were 11.5 ng As/mL versus 0.38 ng/mL for serum and 9.5 ng As/g versus 3.17 ng/g for packed cells (DeKimpe et al, 1993).

B) HEMATOLOGY

1) CHRONIC TOXICITY: The following findings were reported following chronic arsenic exposure: leucocytosis followed by leucopenia with depressed neutrophils; thrombocytopenia; rapidly decreasing hemoglobin indicating hemolytic anemia or GI bleed; aplastic anemia; basophilic stippling of erythrocytes; macrocytosis. Also, a reduction in hemoglobin concentration, reduction in total cell counts, and a rise of mean corpuscular volume (MCV) and hemoglobin mass (MCH), indicating an alteration of heme biosynthetic pathways were present (Rahman et al, 2001).

C) BIOCHEMISTRY

1) CHRONIC TOXICITY: Monitor hepatic and renal function. Elevated serum creatinine transaminases and bilirubin, and depressed haptoglobin levels have been reported following chronic arsenic exposure. Liver histology has shown cirrhosis and noncirrhotic portal fibrosis (Rahman et al, 2001).

D) OTHER

1) CHRONIC TOXICITY: Obtain a skin biopsy as indicated. Carcinomatous changes or Bowen's disease have been described following chronic arsenic exposure (Rahman et al, 2001).

4.1.3)

A) URINARY LEVELS

1) 24-Hour Levels: Even with chelation an unexposed individual should not have more than 100 mcg per 24-hour total urine output.

a) Concentrations of arsenic in 24-hour urine in a male agricultural worker exposed to arsenic from the immersion of his foot in a storage container of concentrated arsenic acid ranged from a high of 2,500 mcg to a low of 160 mcg (McWilliams, 1989).

2) SEAFOOD: Urinary arsenic may be elevated up to 0.2 to 1.7 mg/L within 4 hours after eating some seafoods containing organoarsenical compounds (Baselt, 1997).

a) Mussels gave significant elevations of urinary monomethyl- and dimethylarsonic acid, while ray, cod, and place did not (Buchet et al, 1994).
b) In order to accurately determine urinary arsenic levels, patients should abstain from consuming seafood for 72 to 96 hours prior to urine collection. Also, with samples that contain elevated total arsenic concentrations, laboratories should perform speciation (determination of arsenic as organic or inorganic) prior to reporting results (Kales et al, 2006).

3) VARIATION: In Michigan from 1985 to 1991, 7% of arsenic poisoned patients had some visible signs of arsenic poisoning. Sampled urine arsenic levels ranged from below detection to 198,000 mcg/L, with 36% having greater than 200 mcg/L (Kuslikis et al, 1991).
4) PORPHYRIN EXCRETION: One study reported that no increase in urinary porphyrin excretion was found in a chronically arsenic exposed human population; however, the coproporphyrin/uroporphyrin ratio was observed to be reversed in most exposed individuals due to both an increase in uroporphyrin excretion and a decrease in coproporphyrin excretion. In a study of patients exposed to arsenic in drinking water (0.4 milligrams/liter), reduced coproporphyrin III excretion and increased uroporphyrin excretion were found as compared with subjects whose drinking water contained 0.020 milligrams/liter of arsenic (Garcia-Vargas et al, 1994).
5) A study by the Nofer Institute of Occupational Medicine in Lodz, Poland assessed the relationship between inhalation exposure and urinary excretion of total inorganic arsenic in copper smelting workers. According to the findings, daily exposure to arsenic concentrations of 10 mcg/m(3) and 50 mcg/m(3) led to concentrations of inorganic arsenic metabolites of about 30 mcg/L and 70 mcg/L, respectively (International Archives of Occupational and Environmental Health, 1998).
6) CHRONIC TOXICITY: proteinuria, hematuria and pyuria have been reported following chronic arsenic exposure (Rahman et al, 2001).

4.1.4)

A) OTHER

1) HAIR

a) HAIR/NAIL: Arsenic has been demonstrated in hair and nails within hours after exposure (Lander et al, 1965). NOTE: Hair is continually exposed to the external environment and the presence of a chemical may not be indicative of inhalational or oral exposure.
b) Normal concentration of arsenic in hair and nails is less than 1 mg/kg (Baselt, 1997).
c) Many commercial laboratories performing hair analyses for consumers have not been shown to yield consistent and reliable results (Barrett, 1985).
d) If hair is sent for arsenic quantitation, pubic hair instead of scalp hair should be sent because of the possibility of scalp hair being contaminated with arsenic from the environment (Jenkins, 1966).
e) A comparison of the mean air arsenic concentrations of each occupational exposure group with corresponding arsenic levels in fingernails was highly correlated (Agahian et al, 1990).
f) In a Finnish population, hair arsenic content correlated well with chronic or past exposure to arsenic in drinking water. Hair arsenic concentration increased 0.1 mg/kg for each increase of 10 mcg/L of arsenic in drinking water or 10 to 20 mcg/day of arsenic intake (Kurttio et al, 1998).

2) EXFOLIATED BLADDER CELLS

a) Persons exposed to high levels of arsenic in drinking water had a significantly increased presence of micronuclei in exfoliated bladder cells, even when exposures were near the USA Maximum Contaminant Level (MCL) of 50 mcg of arsenic per liter of water (or 100 mcg in a 24-hour urine) (Moore et al, 1997; Rahman et al, 2001).

3) OTHER

a) CHRONIC TOXICITY: Other diagnostic studies which may be beneficial (based on a patient's clinical presentation) include: ultrasonography of the abdomen, upper gastrointestinal endoscopy, lung function tests, nerve conduction studies (Rahman et al, 2001).

Radiographic Studies

1) Arsenic is radiopaque and an abdominal film should be obtained whenever arsenic ingestion is suspected (Hilfer & Mendel, 1962; Gousios & Adelson, 1959; Lee et al, 1995).

1) Monitor the chest x-ray in patients who develop pulmonary edema.

Treatment

Life Support

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) All patients with acute arsenic toxicity should be admitted.

6.3.1.3) CONSULT CRITERIA/ORAL

A) Consult a medical toxicologist and/or poison center for all potentially significant arsenic exposures.

Monitoring

Oral Exposure

6.5.1)

A) PREHOSPITAL: Remove the contaminated clothing and wash the patient thoroughly.

6.5.2)

A) SUMMARY: Activated charcoal does not bind arsenic well. Gastric lavage and whole bowel irrigation should be considered for confirmed significant ingestions.
B) GASTRIC LAVAGE

1) Aggressive decontamination with gastric lavage is recommended. If X-ray demonstrates arsenic in the lower GI tract, whole bowel irrigation should be considered. Activated charcoal may not bind significant amounts, but is recommended until definitive quantitative data are available. Fluid repletion should be begun as soon as possible.
2) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).

a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.

3) PRECAUTIONS:

a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.

4) LAVAGE FLUID:

a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.

5) COMPLICATIONS:

a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).

6) CONTRAINDICATIONS:

a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.

C) WHOLE BOWEL IRRIGATION (WBI)

a) WHOLE BOWEL IRRIGATION/INDICATIONS: Whole bowel irrigation with a polyethylene glycol balanced electrolyte solution appears to be a safe means of gastrointestinal decontamination. It is particularly useful when sustained release or enteric coated formulations, substances not adsorbed by activated charcoal, or substances known to form concretions or bezoars are involved in the overdose.

1) Volunteer studies have shown significant decreases in the bioavailability of ingested drugs after whole bowel irrigation (Tenenbein et al, 1987; Kirshenbaum et al, 1989; Smith et al, 1991). There are no controlled clinical trials evaluating the efficacy of whole bowel irrigation in overdose.

b) CONTRAINDICATIONS: This procedure should not be used in patients who are currently or are at risk for rapidly becoming obtunded, comatose, or seizing until the airway is secured by endotracheal intubation. Whole bowel irrigation should not be used in patients with bowel obstruction, bowel perforation, megacolon, ileus, uncontrolled vomiting, significant gastrointestinal bleeding, hemodynamic instability or inability to protect the airway (Tenenbein et al, 1987).
c) ADMINISTRATION: Polyethylene glycol balanced electrolyte solution (e.g. Colyte(R), Golytely(R)) is taken orally or by nasogastric tube. The patient should be seated and/or the head of the bed elevated to at least a 45 degree angle (Tenenbein et al, 1987). Optimum dose not established. ADULT: 2 liters initially followed by 1.5 to 2 liters per hour. CHILDREN 6 to 12 years: 1000 milliliters/hour. CHILDREN 9 months to 6 years: 500 milliliters/hour. Continue until rectal effluent is clear and there is no radiographic evidence of toxin in the gastrointestinal tract.
d) ADVERSE EFFECTS: Include nausea, vomiting, abdominal cramping, and bloating. Fluid and electrolyte status should be monitored, although severe fluid and electrolyte abnormalities have not been reported, minor electrolyte abnormalities may develop. Prolonged periods of irrigation may produce a mild metabolic acidosis. Patients with compromised airway protection are at risk for aspiration.

D) ACTIVATED CHARCOAL

1) Preliminary results suggest that activated charcoal may not be of therapeutic value in the treatment of acute arsenic poisoning (Al-Mahasneh QM & Rodgers GC, 1990).

a) One study has reported no significant adsorption to activated charcoal, but specific quantities bound were not stated (Mitchell et al, 1989).
b) Solutions incubated for 120 and 240 minutes at pH 10 to 12 (simulated intestinal juices) showed adsorption of 75% to 80% (Al-Mahasneh QM & Rodgers GC, 1990).

E) ENDOSCOPY

1) Endoscopic removal of adherent arsenic was performed in an adult with acute arsenic poisoning. Attempts to remove arsenic from the stomach were unsuccessful, but colonoscopy was reported successful in removal of arsenic from the ascending colon(Duenas-Laita et al, 2005).

F) GASTROTOMY

1) Gastrotomy with manual removal of adherent arsenic was performed on a patient with persistent evidence of a radio-opaque mass in the stomach, despite gastric lavage and attempted endoscopic removal, after acute arsenic poisoning(Duenas-Laita et al, 2005). It is unclear how much arsenic was removed.

6.5.3)

A) MONITORING OF PATIENT

1) Testing must be correlated with the time of exposure and care must be taken to eliminate possible confounding factors such as food-derived arsenic (fish) or accumulated arsenic in those with chronic renal failure.
2) Diagnosis is based on elevated urinary arsenic levels. A spot urine may be done as a screen prior to chelation but arsenic excretion is intermittent, therefore a 24-hour urine arsenic collection is necessary for definitive diagnosis. A 24-hour urinary arsenic collection exceeding 100 mcg is usually abnormal, even after chelation.
3) Monitor CBC, serum electrolytes, liver enzymes, renal function tests, and a blood arsenic concentration in symptomatic patients.
4) Serial ECGs should be obtained to follow the QTc interval and continuous cardiac monitoring should be instituted in symptomatic patients.
5) Most arsenic compounds are radio-opaque, therefore abdominal X-rays may confirm acute ingestions and guide decontamination.

B) CHELATION THERAPY

1) The use of chelation therapy depends on the clinical condition of the patient and arsenic concentrations in urine, hair, or nails. BAL and succimer are chelating agents used as antidotal therapy for arsenic toxicity. Begin chelation therapy immediately in a severely ill patient with known or suspected acute arsenic poisoning (Ford, 2006).
2) END POINT: Repeat courses of chelation therapy should be prescribed in severe poisonings until the 24-hour urine arsenic level falls below 50 mcg/L (Ford, 2006).

C) DIMERCAPROL

1) Dimercaprol (BAL) is an effective arsenic chelator but has the disadvantages of requiring painful intramuscular injections and having numerous side effects.
2) DOSE: The dose used is dependent on the severity of the patient's symptoms and the urinary arsenic levels.

a) DIMERCAPROL/BAL IN OIL: INDICATIONS: Used for the treatment of mercury (inorganic and elemental), arsenic, and gold poisoning. It is also used in combination with Edetate Calcium Disodium injection to treat patients with severe lead poisoning (Prod Info BAL In Oil intramuscular injection, 2008). Dimercaprol is contraindicated in methyl mercury poisoning (Howland, 2002; Clarkson, 1990).
b) MILD ARSENIC OR GOLD POISONING: DOSE: 2.5 mg/kg 4 times daily for 2 days, 2 times on the third day, and once daily thereafter for 10 days. SEVERE ARSENIC OR GOLD POISONING: DOSE: 3 mg/kg every 4 hours for 2 days, 4 times on the third day, then twice daily thereafter for 10 days. Administered by deep intramuscular injection only (Prod Info BAL In Oil intramuscular injection, 2008).
c) MERCURY POISONING: DOSE: 5 mg/kg initially, then 2.5 mg/kg 1 or 2 times daily for 10 days. Administered by deep intramuscular injection only (Prod Info BAL In Oil intramuscular injection, 2008).
d) ACUTE LEAD ENCEPHALOPATHY: DOSE: 4 mg/kg is given alone in the first dose and thereafter at 4-hour intervals with Edetate Calcium Disodium injection administered at a separate site. For less severe poisoning, dimercaprol dose can be decreased to 3 mg/kg after the first dose. Administered by deep intramuscular injection only. Continue the treatment for 2 to 7 days depending on clinical response (Prod Info BAL In Oil intramuscular injection, 2008). Therapy is generally switched to a less toxic oral chelator as soon as tolerated.
e) ADVERSE EFFECTS: Common effects include pain at the injection site and fever (especially in children). Other effects include hypertension, tachycardia, nausea, vomiting, headache, burning sensations of the mouth and throat, a sensation of constriction in the throat, chest, or hands, conjunctivitis, lacrimation, salivation, tingling of the extremities, diaphoresis, abdominal pain, and anxiety. Dimercaprol injection contains peanut oil. Avoid in patients with peanut allergy (Prod Info BAL In Oil intramuscular injection, 2008). Adverse effects are dose related; they develop in 1% of patients receiving 2.5 mg/kg every 4 to 6 hours, 14% of patients receiving 4 mg/kg every 4 to 6 hours and 65% of patients receiving 5 mg/kg every 4 to 6 hours (Eagle & Magnuson, 1946).
f) PRECAUTIONS: It is generally contraindicated in patients with hepatic insufficiency, with the exception of postarsenical jaundice (Prod Info BAL In Oil intramuscular injection, 2008). May cause hemolysis in G6PD deficient patients. BAL metal chelate disassociates in acid environment; urinary alkalinization is usually recommended. Do not administer with iron therapy as BAL iron complex may cause vomiting (Howland, 2002).

3) EFFICACY

a) CHILDREN: BAL has been reported to result in clinical improvement and decrease in hospital days in children poisoned with arsenic (Woody & Kometani, 1948). It has also been reported to effect complete recovery in a woman and her 20-week fetus after an acute ingestion of inorganic arsenic by the mother (Daya et al, 1989).
b) ANIMALS: BAL has been shown to reduce the organ deposition of arsenic in a rabbit model using subcutaneous injections of Lewisite at the LD10 and LD40 and 4 doses of BAL of 35 mg/kg each (Snider et al, 1990).

D) SUCCIMER

1) INDICATIONS: Succimer is an orally administered chelator approved for use in children with lead poisoning (Prod Info CHEMET(R) oral capsules, 2005). Succimer has been efficacious in children and adults with arsenic poisoning (Cullen et al, 1995; Fournier et al, 1988; Kosnett & Becker, 1987; Lenz et al, 1981).
3) SUCCIMER/DOSE/ADMINISTRATION

a) PEDIATRIC: Initial dose is 10 mg/kg or 350 mg/m(2) orally every 8 hours for 5 days (Prod Info CHEMET(R) oral capsules, 2011).

1) The dosing interval is then increased to every 12 hours for the next 14 days. A repeat course may be given if indicated by elevated blood levels. A minimum of 2 weeks between courses is recommended, unless blood lead concentrations indicate the need for prompt retreatment.
2) Succimer capsule contents may be administered mixed in a small amount of food (Prod Info CHEMET(R) oral capsules, 2011).

b) ADULT: Succimer is not FDA approved for use in adults, however it has been shown to be safe and effective when used to treat adults with poisoning from a variety of heavy metals (Fournier et al, 1988a). Initial dose is 10 mg/kg or 350 mg/m(2) orally every 8 hours for 5 days (Prod Info CHEMET(R) oral capsules, 2011).

1) The dosing interval then is increased to every 12 hours for the next 14 days. A repeat course may be given if indicated by elevated blood levels. A minimum of 2 weeks between courses is recommended, unless the patient's symptoms or blood concentrations indicate a need for more prompt treatment (Prod Info CHEMET(R) oral capsules, 2011).

4) MONITORING PARAMETERS

a) The manufacturer recommends monitoring liver enzymes and complete blood count with differential and platelet count prior to the start of therapy and at least weekly during therapy (Prod Info CHEMET(R) oral capsules, 2011).
b) Succimer therapy did not worsen preexisting borderline abnormal liver enzyme levels in a prospective evaluation of 15 children with lead poisoning (Kuntzelman & Angle, 1992).

5) SUCCIMER/ADVERSE EFFECTS: The following adverse events have occurred in children and adults during clinical trials: nausea, vomiting and diarrhea; transient liver enzyme elevations; rash, pruritus; drowsiness and paresthesia. Events reported infrequently include: sore throat, rhinorrhea, mucosal vesicular eruption, thrombocytosis, eosinophilia, and mild to moderate neutropenia (Prod Info CHEMET(R) oral capsules, 2011).
6) ODOR: Succimer has a sulfurous odor that may be evident in the patient's breath or urine (Prod Info CHEMET(R) oral capsules, 2005).
7) HYPERTHERMIA: One adult developed acute severe hyperthermia associated with hypotension; rechallenge resulted in hyperthermia with shaking chills and hypertension (Marcus et al, 1991).
8) AVAILABLE FORMS: Succimer (Chemet (R)), 100 mg capsules (Prod Info CHEMET(R) oral capsules, 2011).
9) EFFICACY

a) Succimer has been shown to have a safety ratio of 20 times greater than BAL. The total dosage of BAL is limited by its intrinsic toxicity, and the greater safety ratio of succimer allows for longer and more prolonged dosing of succimer (Inns & Rice, 1993).
b) CHRONIC ENVIRONMENTAL ARSENIC POISONING: In a randomized placebo-controlled clinical trial, succimer was NOT EFFICACIOUS in improving a clinical scoring system, skin lesions, or various biochemical laboratory measurements when administered to patients in India with chronic arsenic poisoning from drinking contaminated groundwater (Guha Mazumder et al, 1998).
c) CASE REPORT: In a patient treated with succimer (30 mg/kg/day for 5 days) for long-term ingestion of arsenic, plasma concentrations were unchanged after treatment and renal excretion of arsenic increased 1.5-fold (Fournier et al, 1988).
d) CASE REPORT: A 39-year-old woman developed progressive weakness and peripheral neuropathy leading to quadriplegia and requiring mechanical ventilation following an unknown type of exposure to arsenic. Analysis of her serum and urine revealed elevated arsenic (As) concentrations (290 mcg As/kg [normal less than 2 mcg/kg] and 2000 mcg As/L [normal less than 10 mcg/L], respectively). Despite succimer therapy, 10 mg/kg administered 3 times daily for a total of 33 days over a 45-day period, the patient only showed slow clinical improvement with continued residual paresthesias and weakness in her hands and distal lower extremities 5 years following intoxication(Stenehjem et al, 2007).
e) CASE REPORT: An intravenous preparation of succimer was used to treat a 26-year-old man with multi organ system failure after acute trivalent arsenic overdose. A solution was prepared with 1.6 grams of succimer diluted in 50 mL of sterile water and titrated with 10 N NaOH to pH 7.2 to 7.4 and filtered through a 0.22 micron filter. The solution was administered in 500 mL of 0.9% saline solution as an infusion over 1 hour at a dose of 20 mg/kg/day for 5 days followed by 10 mg/kg/day. The succimer solution was also given via peritoneal dialysis, 20 milligrams/liter of dialysate with 12 L exchanged daily for 5 days (Hantson et al, 1995).

E) PENICILLAMINE

1) USUAL ADULT DOSE

a) 1 to 1.5 g/day given orally in 4 divided doses (Nelson, 2011).

2) USUAL PEDIATRIC DOSE

a) 15 to 30 mg/kg/day in 3 to 4 divided doses. Initially, a small dose may be given to minimize side effects and then increased gradually (eg, 25% of the desired dose in week 1, 50% in week 2, and the full dose by week 3) (Caravati, 2004; Prod Info DEPEN(R) titratable oral tablets, 2009).

3) Patients allergic to penicillin products may have cross-sensitivity to penicillamine (Prod Info DEPEN(R) titratable oral tablets, 2009).
4) Monitor for proteinuria and hematuria; heavy metals may also cause renal toxicity (Prod Info DEPEN(R) titratable oral tablets, 2009).
5) Monitor CBC with differential, platelet count, and hepatic enzymes (Prod Info DEPEN(R) titratable oral tablets, 2009).
6) COMMON SIDE EFFECTS/CHRONIC DOSING: Fever, anorexia, nausea, vomiting, diarrhea, abdominal pain, proteinuria, and myalgia(Prod Info DEPEN(R) titratable oral tablets, 2009).

a) SERIOUS ADVERSE EFFECTS: Nephrotic syndrome, hypersensitivity reactions, leukopenia, thrombocytopenia, aplastic anemia, agranulocytosis, cholestatic hepatitis, and various autoimmune responses (Prod Info DEPEN(R) titratable oral tablets, 2009; Feehally et al, 1987; Kay, 1986).

7) Penicillamine is considered FDA pregnancy category D(Prod Info CUPRIMINE(R) oral capsules, 2004); it should be avoided if possible in pregnant patients.
8) Use of penicillamine throughout pregnancy has been associated with connective tissue abnormalities, hydrocephalus, cerebral palsy, cardiac and great vessel anomalies, webbing of fingers and toes, and arthrogryposis multipex (Linares et al, 1979; Solomon et al, 1977; Anon, 1981; Beck et al, 1981; Rosa, 1986). However, the teratogenic effect when used in low doses or for short periods of time, as in metal chelation, has yet to be determined.
9) EFFICACY

a) CHILDREN: D-penicillamine has been successfully used in acute arsenic poisoning in children (Peterson & Rumack, 1977; Kuruvilla et al, 1975; Watson et al, 1981).

F) UNITHIOL

1) EFFICACY

a) SUMMARY: Unithiol (DMPS) is used in Europe as a chelating agent for heavy metal poisonings (Kruszewska et al, 1996). It appears to be an effective chelator of arsenic in experimental animals (Inns et al, 1990; Kreppel et al, 1990; Aposhian et al, 1984; Hsu et al, 1983; Aposhian et al, 1981) and humans (Goebel et al, 1990; Kew et al, 1993; Moore et al, 1994a; Zilker et al, 1999).
b) INTRAVENOUS DOSING: The dosing regimen depends on the severity of poisoning (Prod Info DIMAVAL(R) IV, IM injection, 2004). See UNITHIOL MANAGEMENT for further information.
c) DMPS/INDICATIONS: Chelating agent for heavy metal toxicities associated with arsenic, bismuth, copper, lead and mercury (Blanusa et al, 2005).
d) DMPS/DOSING

1) ACUTE TOXICITY

a) ADULT ORAL DOSE:

1) 1200 to 2400 mg/day in equally divided doses (100 to 200 mg 12 times daily) (Prod Info DIMAVAL(R) oral capsules, 2004).

b) ADULT INTRAVENOUS DOSE (Arbeitsgruppe BGVV, 1996; Prod Info Dimaval(R) intravenous intramuscular injection solution, 2013):

1) If oral DMPS therapy is not feasible or in severe toxicity, it may be given intravenously.
2) ADMINISTRATION: DMPS should be injected immediately after breaking open the ampule and should not be mixed with other solutions. DMPS should be injected slowly over 3 to 5 minutes. The opened ampules cannot be reused.
3) First 24 hours: 250 mg intravenously every 3 to 4 hours (1500 to 2000 mg total).
4) Day two: 250 mg intravenously every 4 to 6 hours (1000 to 1500 mg total).
5) Day three: 250 mg intravenously every 6 to 8 hours (750 to 1000 mg total).
6) Day four: 250 mg intravenously every 8 to 12 hours (500 to 750 mg total).
7) Subsequent days: 250 mg intravenously every 8 to 24 hours (250 to 750 mg total).
8) Depending on the patient's clinical status, therapy may be changed to the oral route.

c) PEDIATRIC ORAL DOSE (Arbeitsgruppe BGVV, 1996; Blanusa et al, 2005):

1) There are insufficient clinical data regarding the pediatric use of DMPS. It should be used only if medically necessary.
2) Initial dose: 20 to 30 mg/kg/day orally in many equal divided doses.
3) Maintenance dose: 1.5 to 15 mg/kg/day.

d) PEDIATRIC INTRAVENOUS DOSE (Arbeitsgruppe BGVV, 1996; Blanusa et al, 2005; Prod Info Dimaval(R) intravenous intramuscular injection solution, 2013):

1) There are insufficient clinical data regarding the pediatric use of DMPS. It should be used only if medically necessary.
2) If oral DMPS therapy is not feasible or in severe toxicity, it may be given intravenously.
3) ADMINISTRATION: DMPS should be injected immediately after breaking open the ampule and should not be mixed with other solutions. DMPS should be injected slowly over 3 to 5 minutes. The opened ampules cannot be reused.
4) First 24 hours: 5 mg/kg intravenously every four hours (total 30 mg/kg).
5) Day two: 5 mg/kg intravenously every six hours (total 20 mg/kg).
6) Days three and four: 5 mg/kg intravenously every 8 to 24 hours (total 5 to 15 mg/kg).

2) CHRONIC TOXICITY

a) ADULT DOSE

1) 300 to 400 mg/day orally (in single doses of 100 to 200 mg). The dose may be increased in severe toxicity (Arbeitsgruppe BGVV, 1996; Prod Info DIMAVAL(R) oral capsules, 2004).

3) DMPS/ADVERSE REACTIONS

a) Chills, fever, and allergic skin reactions such as itching, exanthema or maculopapular rash are possible (Hla et al, 1992; Prod Info DIMAVAL(R) oral capsules, 2004). Cardiovascular effects such as hypotension, nausea, dizziness or weakness may occur with too rapid injection of DMPS. Hypotensive effects are irreversible at very high doses (300 mg/kg) (Prod Info DIMAVAL(R) oral capsules, 2004; Prod Info Dimaval(R) intravenous intramuscular injection solution, 2013).

e) SOURCES

1) DMPS is not FDA-approved, but is available outside of the US from Heyl Chem-pharm Fabrik in Germany (Prod Info Dimaval(R) intravenous intramuscular injection solution, 2013; Prod Info DIMAVAL(R) oral capsules, 2004). In the US it may be obtained from some compounding pharmacies.

f) CASE SERIES/CHRONIC TOXICITY: In a small (n=10) prospective, randomized, placebo-controlled, single-blind study of untreated patients with chronic arsenicosis following groundwater contamination, unithiol treatment was found to improve some clinical parameters (i.e., weakness, pigmentation and lung disease), and to increase total urinary excretion of arsenic. The treatment dose was 100 mg unithiol (orally) given four times per day for 1 week and repeated in the 3rd, 5th and 7th week of the study (Mazumder et al, 2001).
g) CASE REPORT: A 33-year-old woman developed arsenic poisoning as evidenced by a 1.5 year-history of peripheral neuropathy, pancytopenia, ventricular tachycardia, skin rash, and nail changes. Laboratory data revealed a blood arsenic concentration of 5.6 mcg/dL. Despite administration of succimer, the neuropathy continued to progress to facial paresis, severe weakness in all 4 extremities, and respiratory failure. Succimer was then discontinued, and unithiol was initiated at a dosage regimen of 250 mg IV every 4 hours. Twenty-four hours after beginning unithiol therapy, urinary excretion of arsenic increased to 300 mcg/L from a baseline of 101 mcg/L. Within 48 hours, the patient's neuropathy improved and, 10 days later, she was discharged in a wheelchair. At her 3-month follow-up, the patient continued to have residual paresthesias and weakness in her lower extremities, but she was able to walk without assistance, and by 1 year she was back at work with mild residual weakness and paresthesiae(Wax & Thornton, 2000a).

G) HYPOTENSIVE EPISODE

1) Hypotension from acute arsenic ingestion is likely due to intravascular volume depletion from vomiting, diarrhea, or third spacing of fluids.
2) The initial treatment should consist of adequate volume replacement with crystalloid, with the addition of blood products in patients with significant gastrointestinal blood loss. Place the patient supine until hypotension is corrected.
3) Aggressive monitoring of volume status should be undertaken even in the absence of hypotension initially. Bladder catheterization to monitor hourly urine output, a central venous catheter, or a Swan-Ganz catheter should be used as clinically warranted.
4) Pressors should be used only if volume replacement does not reverse the hypotension.
5) DOPAMINE

a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).

6) NOREPINEPHRINE

a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
b) DOSE

1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

H) TACHYCARDIA

1) Tachycardia may be a response to hypovolemia and should be treated initially with fluid replacement as clinically warranted.

I) VENTRICULAR ARRHYTHMIA

1) VENTRICULAR DYSRHYTHMIAS SUMMARY

a) Obtain an ECG, institute continuous cardiac monitoring and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders (particularly hypokalemia, hypocalcemia, and hypomagnesemia). Lidocaine and amiodarone are generally first line agents for stable monomorphic ventricular tachycardia, particularly in patients with underlying impaired cardiac function. Amiodarone should be used with caution if a substance that prolongs the QT interval and/or causes torsades de pointes is involved in the overdose. Unstable rhythms require immediate cardioversion.

2) LIDOCAINE

a) LIDOCAINE/INDICATIONS

1) Ventricular tachycardia or ventricular fibrillation (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010; Vanden Hoek et al, 2010).

b) LIDOCAINE/DOSE

1) ADULT: 1 to 1.5 milligrams/kilogram via intravenous push. For refractory VT/VF an additional bolus of 0.5 to 0.75 milligram/kilogram can be given at 5 to 10 minute intervals to a maximum dose of 3 milligrams/kilogram (Neumar et al, 2010). Only bolus therapy is recommended during cardiac arrest.

a) Once circulation has been restored begin a maintenance infusion of 1 to 4 milligrams per minute. If dysrhythmias recur during infusion repeat 0.5 milligram/kilogram bolus and increase the infusion rate incrementally (maximal infusion rate is 4 milligrams/minute) (Neumar et al, 2010).

2) CHILD: 1 milligram/kilogram initial bolus IV/IO; followed by a continuous infusion of 20 to 50 micrograms/kilogram/minute (de Caen et al, 2015).

c) LIDOCAINE/MAJOR ADVERSE REACTIONS

1) Paresthesias; muscle twitching; confusion; slurred speech; seizures; respiratory depression or arrest; bradycardia; coma. May cause significant AV block or worsen pre-existing block. Prophylactic pacemaker may be required in the face of bifascicular, second degree, or third degree heart block (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010).

d) LIDOCAINE/MONITORING PARAMETERS

1) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).

3) AMIODARONE

a) AMIODARONE/INDICATIONS

1) Effective for the control of hemodynamically stable monomorphic ventricular tachycardia. Also recommended for pulseless ventricular tachycardia or ventricular fibrillation in cardiac arrest unresponsive to CPR, defibrillation and vasopressor therapy (Link et al, 2015; Neumar et al, 2010). It should be used with caution when the ingestion involves agents known to cause QTc prolongation, such as fluoroquinolones, macrolide antibiotics or azoles, and when ECG reveals QT prolongation suspected to be secondary to overdose (Prod Info Cordarone(R) oral tablets, 2015).

b) AMIODARONE/ADULT DOSE

1) For ventricular fibrillation or pulseless VT unresponsive to CPR, defibrillation, and a vasopressor therapy give an initial dose of 300 mg IV followed by 1 dose of 150 mg IV. For stable ventricular tachycardias: Infuse 150 milligrams over 10 minutes, and repeat if necessary. Follow by a 1 milligram/minute infusion for 6 hours, then a 0.5 milligram/minute. Maximum total dose over 24 hours is 2.2 grams (Neumar et al, 2010).

c) AMIODARONE/PEDIATRIC DOSE

1) Infuse 5 milligrams/kilogram as a bolus for pulseless ventricular tachycardia or ventricular fibrillation; may repeat twice up to 15 mg/kg. Infuse 5 milligrams/kilogram over 20 to 60 minutes for perfusing tachycardias. Maximum single dose is 300 mg. Routine use with other drugs that prolong the QT interval is NOT recommended (Kleinman et al, 2010).

d) ADVERSE EFFECTS

1) Hypotension and bradycardia are the most common adverse effects (Neumar et al, 2010).

J) TORSADES DE POINTES

1) SUMMARY

a) Withdraw the causative agent. Hemodynamically unstable patients with Torsades de pointes (TdP) require electrical cardioversion. Emergent treatment with magnesium (first-line agent) or atrial overdrive pacing is indicated. Detect and correct underlying electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia). Correct hypoxia, if present (Drew et al, 2010; Neumar et al, 2010; Keren et al, 1981; Smith & Gallagher, 1980).
b) Polymorphic VT associated with acquired long QT syndrome may be treated with IV magnesium. Overdrive pacing or isoproterenol may be successful in terminating TdP, particularly when accompanied by bradycardia or if TdP appears to be precipitated by pauses in rhythm (Neumar et al, 2010). In patients with polymorphic VT with a normal QT interval, magnesium is unlikely to be effective (Link et al, 2015).

2) MAGNESIUM SULFATE

a) Magnesium is recommended (first-line agent) for the prevention and treatment of drug-induced torsades de pointes (TdP) even if the serum magnesium concentration is normal. QTc intervals greater than 500 milliseconds after a potential drug overdose may correlate with the development of TdP (Charlton et al, 2010; Drew et al, 2010). ADULT DOSE: No clearly established guidelines exist; an optimal dosing regimen has not been established. Administer 1 to 2 grams diluted in 10 milliliters D5W IV/IO over 15 minutes (Neumar et al, 2010). Followed if needed by a second 2 gram bolus and an infusion of 0.5 to 1 gram (4 to 8 mEq) per hour in patients not responding to the initial bolus or with recurrence of dysrhythmias (American Heart Association, 2005; Perticone et al, 1997). Rate of infusion may be increased if dysrhythmias recur. For persistent refractory dysrhythmias, a continuous infusion of up to 3 to 10 milligrams/minute in adults may be given (Charlton et al, 2010).
b) PEDIATRIC DOSE: 25 to 50 milligrams/kilogram diluted to 10 milligrams/milliliter for intravenous infusion over 5 to 15 minutes up to 2 g (Charlton et al, 2010).
c) PRECAUTIONS: Use with caution in patients with renal insufficiency.
d) MAJOR ADVERSE EFFECTS: High doses may cause hypotension, respiratory depression, and CNS toxicity (Neumar et al, 2010). Toxicity may be observed at magnesium levels of 3.5 to 4.0 mEq/L or greater (Charlton et al, 2010).
e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respiratory rate, motor strength, deep tendon reflexes, serum magnesium, phosphorus, and calcium concentrations (Prod Info magnesium sulfate heptahydrate IV, IM injection, solution, 2009).

3) OVERDRIVE PACING

a) Institute electrical overdrive pacing at a rate of 130 to 150 beats per minute, and decrease as tolerated. Rates of 100 to 120 beats per minute may terminate torsades (American Heart Association, 2005). Pacing can be used to suppress self-limited runs of TdP that may progress to unstable or refractory TdP, or for override refractory, persistent TdP before the potential development of ventricular fibrillation (Charlton et al, 2010). In a case series overdrive pacing was successful in terminating TdP associated with bradycardia and drug-induced QT prolongation (Neumar et al, 2010).

4) POTASSIUM REPLETION

a) Potassium supplementation, even if serum potassium is normal, has been recommended by many experts (Charlton et al, 2010; American Heart Association, 2005). Supplementation to supratherapeutic potassium concentrations of 4.5 to 5 mmol/L has been suggested, although there is little evidence to determine the optimal range in dysrhythmia (Drew et al, 2010; Charlton et al, 2010).

5) ISOPROTERENOL

a) Isoproterenol has been successful in aborting torsades de pointes that was resistant to magnesium therapy in a patient in whom transvenous overdrive pacing was not an option (Charlton et al, 2010) and has been successfully used to treat torsades de pointes associated with bradycardia and drug induced QT prolongation (Keren et al, 1981; Neumar et al, 2010). Isoproterenol may have a limited role in pharmacologic overdrive pacing in select patients with drug-induced torsades de pointes and acquired long QT syndrome (Charlton et al, 2010; Neumar et al, 2010). Isoproterenol should be avoided in patients with polymorphic VT associated with familial long QT syndrome (Neumar et al, 2010).
b) DOSE: ADULT: 2 to 10 micrograms/minute via a continuous monitored intravenous infusion; titrate to heart rate and rhythm response (Neumar et al, 2010).
c) PRECAUTIONS: Correct hypovolemia before using; contraindicated in patients with acute cardiac ischemia (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).

1) Contraindicated in patients with preexisting dysrhythmias; tachycardia or heart block due to digitalis toxicity; ventricular dysrhythmias that require inotropic therapy; and angina. Use with caution in patients with coronary insufficiency (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).

d) MAJOR ADVERSE EFFECTS: Tachycardia, cardiac dysrhythmias, palpitations, hypotension or hypertension, nervousness, headache, dizziness, and dyspnea (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respirations and central venous pressure to guide volume replacement (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).

6) OTHER DRUGS

a) Mexiletine, verapamil, propranolol, and labetalol have also been used to treat TdP, but results have been inconsistent (Khan & Gowda, 2004).

7) AVOID

a) Avoid class Ia antidysrhythmics (eg, quinidine, disopyramide, procainamide, aprindine), class Ic (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics (eg, N-acetylprocainamide, sotalol) since they may further prolong the QT interval and have been associated with TdP.

K) NEUROPATHY

1) Early administration (within 18 hours of acute exposure) of BAL may be effective in preventing arsenical neuropathy (Jenkins, 1966). However, once neuropathy has developed (usually 1 to 3 weeks after acute exposure), chelation with BAL may not be effective in reversing it (Heyman et al, 1956; Donofrio et al, 1987a; Le Quesne & McLeod, 1977).
2) Unithiol (DMPS, dimercaptopropanesulfonic acid) may be superior in the treatment of neuropathy (Wax & Thornton, 2000; Moore et al, 1994)
3) Physical therapy may be helpful for patients with established arsenical neuropathies.

L) CORTICOSTEROID

1) MELARSOPROL ENCEPHALOPATHY: Only 4 percent of those patients given corticosteroids (prednisolone, not more than 40 milligrams daily) developed melarsoprol encephalopathy compared to approximately 33 percent in those patients receiving no steroids in a prospective randomized trial involving 600 patients with parasitology-confirmed Trypanosoma brucei gambiense infections (Pepin et al, 1989).

Inhalation Exposure

6.7.1)

A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.

6.7.2)

A) ACUTE LUNG INJURY

1) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
2) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).

a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)

3) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
4) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
5) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
6) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
7) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).
8) Refer to TREATMENT/ORAL EXPOSURE section for more information.

B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Eye Exposure

6.8.1)

A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

6.8.2)

A) OPHTHALMIC EXAMINATION AND EVALUATION

1) SYSTEMIC TOXICITY: No cases of systemic arsenic poisoning following only eye exposure have been reported.
2) CONSULTATION: If significant eye irritation is present, prolonged initial flushing and early ophthalmologic consultation are advisable.
3) Refer to TREATMENT/ORAL EXPOSURE section for more information.

B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Dermal Exposure

6.9.1)

A) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

6.9.2)

A) IRRITATION SYMPTOM

1) Treat dermal irritation or burns with standard topical therapy. Patients developing dermal hypersensitivity reactions may require treatment with systemic or topical corticosteroids or antihistamines.
2) Workers with significant arsenical dermatitis, ulcerations, or dermatoses may be overexposed and may need to be precluded from further exposure.
3) Refer to TREATMENT/ORAL EXPOSURE section for more information.

B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Enhanced Elimination

1) Arsenic is poorly dialyzable. Hemodialysis should only be considered for arsenic toxicity accompanied by renal failure (Giberson et al, 1976).
2) In another study, Zilker et al (1999) reported that hemodialysis and CAVHDF did not significantly alter arsenic kinetics in a 24-year-old man who had accidentally ingested arsenic residue with an initial serum arsenic level of 245.8 micrograms/liter (Zilker et al, 1999). Dimercaptopropane sulfonate (DMPS) 1.2 grams was also given during the first two days of enhanced elimination therapy. During the first 87 hours following admission, 89.67 mg of arsenic was recovered in the urine, while the first hemodialysis removed 0.168 mg of arsenic and 0.061 mg was found in the CAVHDF dialysate.

a) Renal function remained normal throughout the period, and the authors suggested that unithiol was an effective therapy for arsenic poisoning when no kidney failure was present. One limitation of the study, however, was that no urinary levels were obtained prior to unithiol treatment.

3) Dialysis clearance rates of arsenic in two patients was 76 and 87 milliliters/minute (Vaziri et al, 1980).
4) Hemodialysis was instituted 4 hours postadmission in a 30-year-old man who ingested 6 ounces of a rodenticide containing arsenous oxide 1.5 percent (approximately 2,150 milligrams of metallic arsenic) although the patient exhibited no evidence of renal impairment (Fesmire et al, 1988).
5) Hemodialysis and continuous arterio-venous hemodiafiltration were found to remove negligible amounts of arsenic in an adult who maintained normal renal function after poisoning with arsenic (Zilker et al, 1999).

Abstracts

Range Of Toxicity

Maximum Tolerated Exposure

1) Estimates of acute oral toxic doses of various arsenic compounds range from 1 mg to 10 grams.
2) Pentavalent arsenic may be converted in vivo to trivalent arsenic. Trivalent arsenic (arsenite) is more toxic in animals than the pentavalent form (arsenate). However, significant toxicity may occur with large amounts of pentavalent salts in humans (Morgan, 1993).
3) A 30-year-old man survived an ingestion of 6 ounces of "Blue Ball Rat Killer" containing 1.5% arsenous oxide (2,150 milligrams metallic arsenic per 6 ounces) with aggressive therapy (fluid resuscitation, chelation, and hemodialysis) (Fesmire et al, 1988).
4) In a case series of 149 arsenate ant-killer ingestions from Minnesota, mainly in children under age three, no treatment was provided and no adverse effects occurred on follow-up 4 to 6 months following exposure. In two cases, urine arsenic levels without chelation reached 3500 and 5819 mcg/24 hours and no sequelae were observed, suggesting that many small arsenate ingestions may remain asymptomatic (Kingston et al, 1993).

Workplace Standards

1) Not Listed

1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): 1 ; Listed as: Arsenic pentoxide

a) 1 : The agent (mixture) is carcinogenic to humans. The exposure circumstance entails exposures that are carcinogenic to humans. This category is used when there is sufficient evidence of carcinogenicity in humans. Exceptionally, an agent (mixture) may be placed in this category when evidence of carcinogenicity in humans is less than sufficient but there is sufficient evidence of carcinogenicity in experimental animals and strong evidence in exposed humans that the agent (mixture) acts through a relevant mechanism of carcinogenicity.

4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
5) MAK (DFG, 2002): Not Listed
6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

1) Not Listed

Toxicity Information

7.7.1)

A) LD50- (ORAL)MOUSE:

1) 55 mg/kg ((RTECS, 2000))

B) LD50- (ORAL)RAT:

1) 8 mg/kg ((RTECS, 2000))

Summary

Minimum Lethal Exposure

1) A concentration of 10 ppm of arsenic pentoxide in water presents an acute hazard (OHM/TADS , 2000).
2) A rapid die-off was noted in breeding colonies of rats and mice when 5 mg/L of arsenic pentoxide was added to the drinking water (OHM/TADS , 2000).
3) One mg/kg of ingested arsenic may be lethal in a child (Woody & Kometani, 1948).
4) The smallest recorded lethal dose of arsenic is approximately 130 mg (Bingham et al, 2001; OHM/TADS , 2001).
5) As little as 20 mg of arsenic may produce life-threatening toxicity (Hutton & Christians, 1983; Schoolmeester & White, 1980; Zaloga et al, 1970).

1) Between 1966 and 1979, 61 cases of accidental sodium arsenite poisoning, including 11 patients who were hospitalized and 24 fatal cases in adults and children, were reported to the EPA's Pesticide Incident Monitoring System (PIMS) (EPA, 1988).

Pharmacology Toxicology

Physicochemical

Physical Characteristics

Molecular Weight

Animal Toxicology

References

General Bibliography

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ARSENIC PENTOXIDE

Classification | Detailed evidence-based information

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Available Forms Sources

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Monitoring Parameters Levels

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Maximum Tolerated Exposure

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Toxicity Information

Summary

Minimum Lethal Exposure

Physical Characteristics

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General Bibliography