89: Arsenic

Arsenic poisoning can be unintentional, suicidal, homicidal, occupational, environmental, or iatrogenic.^{108,109,141,165} Mass poisonings have occurred. Nearly 400 residents of Hong Kong fell ill after eating contaminated bread from the Esing Bakery in 1857; two bakery foremen were thought to have tampered with the recipe.⁸⁹ The 1900 Staffordshire beer epidemic in England saw 6000 beer drinkers fall ill and 70 die from beer brewed with sugar made with arsenic-contaminated sulfuric acid.¹⁰⁸ In Wakayama, Japan, 67 people were poisoned by eating intentionally contaminated curry at a festival in 1998.²²³ In 2003, the largest recent outbreak of arsenic poisoning in the United States occurred in New Sweden, Maine, when intentionally adulterated church coffee resulted in the death of one parishioner and the hospitalization of an additional 15 victims.¹⁹ Arsenic trioxide (As₂O₃) reemerged as a treatment for acute promyelocytic leukemia (APML) in the 1990s after physicians in Harbin, China, found a high remission rate in patients given, a crude As₂O₃ infusion.^126,259

Contaminated soil, water, and food are the primary sources of arsenic for the general population. Pentavalent arsenic (As⁵⁺) is the most common inorganic form in the environment.⁵⁷ Inorganic arsenic exposure from food is generally low and usually occurs from soil-derived foods such as rice and produce.^{32,199,250,258} Exposure to organic arsenic compounds of low toxicity occurs from consumption of algae, fish, and shellfish. In the past two decades, consumption of contaminated water has emerged as the primary cause of large-scale outbreaks of chronic arsenic toxicity. Arsenic leaches from certain minerals and ores, as well as from industrial waste.¹⁴⁸ In Ban­gla­desh, millions of people have been poisoned by drinking water from wells contam­inated with arsenic leached from ground minerals.¹⁷⁰ Ironically, the wells were dug to obtain safer groundwater. Hydroarsenicism is also reported in Chile, Taiwan, Brazil, India, Mexico, and Argentina.^{35,51,57,102,148,170,239} In 2001, the US Environmental Protection Agency decreased the maximum contaminant concentration of arsenic in drinking water to 10 parts per billion (ppb), or10 μg/L, after statistical modeling indicated an increased risk of lung and bladder cancer from water contaminated with arsenic at the formerly acceptable concentration of 50 ppb.⁶⁶ The World Health Organization also recommends a maximum concentration of 10 ppb.

Arsenic is a metalloid that exists in multiple forms: elemental, gaseous (arsine), organic, and inorganic [As³⁺ (trivalent, or arsenite) and As⁵⁺ (pentavalent, or arsenate)]. Tables 89–1 and 89–2 list sources of arsenic and regulatory standards about arsenic, respectively. Arsenic metal is considered nonpoisonous because of its insolubility in water and, therefore, bodily fluids.¹⁹⁸ Arsine, which is highly toxic, is discussed in Chap. 124. Trivalent arsenicals include arsenic trioxide (As₂O₃), tetra-arsenic tetrasulfide (realgar; As₄S₄), and diarsenic trisulfide (orpiment; As₂S₃). Realgar and orpiment were used by the Chinese to treat malignancies, diarrhea, and infections of the chest and liver.¹³⁹ Organic arsenicals vary in toxicity. Arsenobetaine, which is synthesized from inorganic arsenic by fish and crustaceans, and arsenosugars, which are synthesized by fish, crustaceans, and algae, have very low toxicity.^12,63,131 In contrast, the organoarsenical medication melarsoprol, used to treat the meningoencephalitic stage of African trypanosomiasis, is highly toxic and similar to inorganic arsenite.^27,187

As₂O₃ has been used successfully to treat APML. The role of arsenic in our pharmacopeia is expanding; its efficacy in treating various other leukemias, lymphomas, and multiple myeloma, as well as a variety of solid tumors such as breast cancer, colon cancer, lung cancer, hepatocellular carcinoma, colorectal cancer, renal cell carcinoma, and osteosarcoma is being studied.^38,122,159

As₂O₃ is administered therapeutically for treating APML in doses of 0.15 to 0.16 mg/kg/d by either the intravenous or oral route.^{124,126,201,202,205} At this dose its beneficial effects occur predominantly by initiating cellular apoptosis when arsenic concentrations reach 0.5 to 2.0 μmol/L. Apoptosis is triggered by several mechanisms. The trivalent arsenic (As³⁺) ion binds to mitochondrial membrane sulfhydryl (SH) groups, damaging mitochondrial membranes and collapsing membrane potentials. Cytochrome c is released from the damaged mitochondria, with subsequent activation of caspases 9, 3, and 8 and initiation of apoptosis. Cells may be more susceptible if the intracellular concentrations of catalase and glutathione peroxidase (H₂O₂ scavenging enzymes) and glutathione-S-transferase (responsible for conjugating glutathione to xenobiotics) are reduced.^{44,65,79,110,191} As₂O₃ also facilitates apoptosis by down-regulating gene expression of BCL2, a prosurvival protein that protects against apoptosis.³⁶ Finally, As₂O₃ can arrest cells early in mitosis, subsequently leading to apoptosis.⁹²

Low-dose As₂O₃treatment (0.08 mg/kg/d) beneficially promotes cell differentiation of APL cells when arsenic concentrations reach 0.1 to 2.0 μmol/L. This differentiation is impaired by the promyelocytic leukemia-retinoic acid receptor α (PML-RARα) oncoprotein. This oncoprotein results from the APML-defining translocation of chromosomes 15 and 17. The PML portion of this oncoprotein plays a key role in leukemogenesis by interfering with RARα activity that is essential for normal myeloid cellular development. As³⁺ degrades this PML portion, freeing RARα to facilitate cell differentiation.^44,154,161

Melarsoprol is a trivalent organic arsenical compound used in Africa and parts of Europe to treat the meningoencephalitic stages of both species of African trypanosomes. It is ineffective against American trypanosomiasis and is available in the United States only directly from the Centers for Disease Control and Prevention (CDC), as it is not approved by the US Food and Drug Administration (FDA). The mechanism of action is still poorly understood but may be related to inhibition of glycolysis and oxidation-reduction reactions. The pharmaceutical compound also contains dimercaprol (BAL), which seems to reduce toxicity without diminishing effectiveness. The therapeutic use of melarsoprol can produce many of the toxic effects that occur with inorganic arsenic, including fever, encephalopathy, and acute cerebral edema with seizures and coma. Whether these effects are caused by drug toxicity or by an immune reaction elicited by trypanosomal antigens is unknown.^27,171,187 Other adverse effects include vomiting, abdominal pain, peripheral neuropathy with hypersensitivity reactions, hypertension, myocardial damage, and albuminuria. Hemolysis can occur in patients with glucose-6-phosphate dehydrogenase deficiency, and erythema nodosum can occur in patients with leprosy.^27,171 In a study of the usefulness of melarsoprol as a treatment for refractory or advanced leukemia, efficacy was very limited, and reported adverse effects included fatigue, vomiting, diarrhea, vertigo, fever, seizures, headache, back pain, and injection site pain.²⁰⁶

Investigations of the pathophysiologic effects induced by toxic doses of arsenic are discussed below. The apoptotic mechanisms³⁰ thought to be responsible for some therapeutic effects of As₂O₃ have not been well studied in toxicity models, but limited evidence suggests that cell necrosis may be more important.

Trivalent Arsenic

The primary biochemical effect of As³⁺ is inhibition of the pyruvate dehydrogenase (PDH) complex (Fig. 89–1). Normally, dihydrolipoamide is recycled to lipoamide, a necessary cofactor in the conversion of pyruvate to acetylcoenzyme A (acetyl-CoA). As³⁺ binds the sulfhydryl groups of dihydrolipoamide, blocking lipoamide regeneration.¹⁸⁶ Acetyl-CoA is a central molecule in metabolism, and the resulting decrease leads to several deleterious effects:

• Decreased citric acid cycle activity and thus decreased adenosine triphosphate (ATP) production.

• Disruption of oxidative phosphorylation, which leads to production of hydrogen peroxide and oxygen radicals.

• Decreased gluconeogenesis that can worsen hypoglycemia. Pyruvate carboxylase catalyzes the conversion of pyruvate to oxaloacetate (initial step in gluconeogenesis), and this reaction requires the carboxylation of biotin, a CO₂ carrier attached to pyruvate carboxylase. Biotin cannot be carboxylated unless acetyl-CoA is attached to the enzyme.^187,211

In the citric acid cycle, oxidation of α-ketoglutarate to succinyl-CoA uses an α-ketoglutarate dehydrogenase complex that contains the same cofactors as the PDH complex, including lipoamide. Succinyl-CoA is necessary for production of porphyrins and amino acids, and deficiency may contribute to the anemia and wasting that occurs with chronic arsenic poisoning. Arsenic inhibition of thiolase, the catalyst for the final step in fatty acid oxidation, also impairs ATP production. Diminished fatty acid oxidation results in decreased acetyl-CoA, in the loss of the reduced form of nicotinamide adenine dinucleotide (NADH) and the reduced form of ­flavin adenine dinucleotide (FADH₂) (electron carriers reduced during fatty acid breakdown whose subsequent oxidation yields ATP). As³⁺ also inhibits glutathione synthetase, glucose-6-phosphate dehydrogenase (required to produce nicotinamide adenine dinucleotide phosphate {NADPH}), and glutathione reductase.⁸ These inhibitions result in decreased concentrations of reduced glutathione, which is required to facilitate arsenic metabolism, protect red blood cells (RBCs) from oxidative damage, maintain hemoglobin in the ferrous state, and scavenge hydrogen peroxide and other organic peroxides.

Arsenic affects cardiac repolarization currents. When toxicity occurs, the result is ventricular dysrhythmias, including torsade de pointes. An in vitro study of cells exposed to As³⁺ demonstrated blockade of the delayed rectifier channels I_Ks and I_Kr. Interestingly, activation of I_K-ATP , a weak inward rectifier channel, also occurred; this activation could potentially counteract some of the effects of As³⁺ on the I_Ks and I_Kr channels.⁶⁰

Animal experiments with phenylarsine oxide, a trivalent arsenical, demonstrate inhibition of insulin-induced glucose transport involving vicinal (adjacent) sulfhydryl groups, as well as β cell damage in pancreatic islets attributed to inhibition of the α-ketoglutarate dehydrogenase complex.²⁵ The impaired glucose transport, plus the inhibited gluconeogenesis, can lead to glycogen depletion and hypoglycemia.¹⁸⁸ Several animal experiments indicate improved central nervous system (CNS) glucose content¹⁸⁷ and increased in survival time with glucose treatment.¹⁸⁷

Effects on RBCs include decreased membrane fluidity and ATP depletion.²⁴⁶ Chronic arsenic exposure is associated with vascular disease; in vitro studies demonstrate inhibition of endothelial cell proliferation and glycoprotein synthesis in addition to lipid peroxidation.³⁷ A study on rodent and human platelets demonstrates increased platelet aggregation and arterial thrombosis.¹³³ Noncirrhotic hepatic portal fibrosis can develop. In a controlled study where mice chronically ingested water containing equal parts As³⁺ and As⁵⁺ for up to 15 months, the development of portal fibrosis was preceded by decreased hepatic glutathione (GSH) concentration, increased lipid peroxidation, and diminished concentrations or activities of numerous enzymes involved in regenerating GSH or scavenging free radicals.¹⁹⁶ Proposed mechanisms by which arsenic induces cancer include DNA damage induced by a dimethyl sulfide (DMS)-derived peroxyl radical, gene amplification, replacing phosphate in DNA during replication, increased cell proliferation, and decreased DNA repair efficiency.^17,115,249 Experimental evidence and human studies support a number of etiologic or contributing factors for skin keratosis and cancer,¹ including chronic stimulation of keratinocyte-derived growth factors such as transforming growth factor-α (TGF-α), impaired methylation, mutation in the p53 tumor-suppressor gene, inhibition of poly(adenosine diphosphate {ADP}-ribose) polymerase vital for DNA repair, and interference with mitotic spindle and microtubular function.^{7,81,105,137,248} Pigmentary changes also occur, and hyperpigmentation is attributed to increased melanin.

Pentavalent Arsenic

Several mechanisms contribute to the toxicity of As⁵⁺. As⁵⁺ can be reduced to As³⁺.^106,231 As⁵⁺ also resembles phosphate chemically and structurally, may share a common transport system for cellular uptake with phos­phate,¹⁰⁶ and can inhibit oxidative phosphorylation by substituting for inorganic phosphate (P_i) in the glycolysis reaction catalyzed by glyceraldehyde 3-phosphate dehydrogenase (Fig. 89–2).^34,189 The resulting unstable product, 1-arseno-3-phosphoglycerate, spontaneously hydrolyzes to 3-phosphoglycerate, so glycolysis continues but the ATP normally produced during conversion of 1,3-bisphosphoglycerate to 3-phosphoglycerate is lost. Uncoupling may also occur if ADP forms ADP-arsenate, instead of ATP, in the presence of As⁵⁺. The ADP-arsenate rapidly hydrolyzes, thus uncoupling oxidative phosphorylation.

Absorption

Inorganic arsenic is tasteless and odorless and can be absorbed by the gastrointestinal (GI), respiratory, intravenous, and mucosal routes. GI absorption is facilitated by increased solubility and smaller particle size, and it occurs predominantly in the small intestine, followed by the colon. Poorly soluble trivalent compounds such as As₂O₃ are less well absorbed than more soluble trivalent and pentavalent compounds that, in aqueous solution, have an oral bioavailability greater than 90%. Therefore, when placed in an aqueous solution, As₂O₃ is more toxic than an identical dose of undissolved As₂O₃ eaten in food because of its failure to dissolve, thereby limiting absorption.²²⁸ Organic arsenicals tend to be well absorbed; for example, a rodent study demonstrated approximately 70% GI absorption of the commonly used organic arsenical herbicide, dimethylarsinic acid (cacodylic acid).²⁰⁸ Systemic absorption via the respiratory tract depends on the particulate size, as well as the arsenic compound and its solubility. Large, nonrespirable particles are cleared from the airways by ciliary action and swallowed, allowing GI absorption to occur. Respirable particles lodging in the lungs can be absorbed over days to weeks or remain unabsorbed for years.^28,243 Dermal penetration of arsenic through intact skin does not pose a risk for acute toxicity but potentially may be problematic with chronic application. Arsenic acid (H₃AsO₄) applied to intact skin in rhesus monkeys resulted in absorption of a mean of 2.0% to 6.4% of the applied dose.²⁴¹ Skin irritation and damage may increase systemic absorption.^78,190

Pharmacokinetics of Arsenic Trioxide

Intravenous administration of a single 10-mg dose of As₂O₃ to eight patients showed mean pharmacokinetic values as follows: maximum plasma concentration (Cp_max) of 6.85 μmol/L, α elimination half-life (t_1/2 α) of 0.89 ± 0.29 hours, and β elimination half-life (t_1/2 β) of 12.13 ± 3.31 hours.²⁰² In six patients, only 1% to 8% of the daily dose was eliminated in a 24-hour urine. Repeat pharmacokinetic studies on day 30 of treatment were not statistically different.²⁰² Another study of patients receiving a single dose of 5 mg of As₂O₃ intravenously demonstrated mean pharmacokinetic values as follows: Cp_max of 2.6 μmol/L, t_1/2 α of 1.41 hours, t_1/2 β of 9.41 hours, serum clearance of 1.98 L/h, and area under the plasma drug concentration versus time curve (AUC) of 12.7 μmol/L/h. A single dose of 10 mg intravenously showed a Cp_max of 6.7 ± 0.3 μmol/L.²⁰¹ As₂O₃ 10 mg given orally for APML demonstrated total plasma and blood AUC values that were 99% and 87%, respectively, of the corresponding values reported for a 10-mg intravenous dose administered in the same nine patients.¹²⁴

A study in humans receiving intravenous radioarsenic isotope (⁷⁴ As) showed arsenic clearing from the blood in three phases:

• Phase 1 (2 to 3 hours)—Arsenic is rapidly cleared from the plasma with a t_1/2 of 1 to 2 hours; more than 90% may be cleared during this phase because of redistribution to tissue and renal elimination.

• Phase 2 (3 hours to 7 days)—A more gradual plasma decline occurs, with an estimated t_1/2 of 30 hours.

• Phase 3 (10 or more days)—Clearance continues from the plasma slowly with an estimated t_1/2 of 300 hours.¹⁵⁰

The rapid clearance in phases 1 and 2 explains why blood testing for arsenic is unreliable, except early in acute poisoning.

Initial distribution is predominantly to liver, kidney, muscle, and skin. The skin is rich in sulfhydryl groups; the elimination t_1/2 of arsenic by the skin was estimated to be one month in a rabbit study.⁶¹ Distribution to brain also occurs quickly. In the⁷⁴ As study, 0.30% of the administered dose was found in brain biopsy samples in the first hour postinfusion. This peak declined to 0.16% by day 7.¹⁵⁰ Ultimately, arsenic distributes to all tissues. In the single patient in this study who was followed for 18 days, 96.6% of the total injected arsenic dose was recovered in the urine. Fecal arsenic recovery was less than 1% of the total dose.¹⁵⁰ Other studies in humans demonstrate renal arsenic elimination of 46% to 68.9% within the first 5 days postingestion.^{29,32,111,179} Approximately 30% is eliminated with a half-life of greater than one week, while the remainder is slowly excreted with a half-life of greater than one month.^29,149 Fecal elimination is considerably less, with reported amounts as much as 6.1% in humans.²¹³ Canine studies have revealed that the mechanisms of urinary elimination of unchanged arsenic and its methylated metabolites are via glomerular filtration and tubular secretion; active reabsorption also occurs.²²¹

Arsenic crosses the placenta and accumulates in the fetus,¹⁴⁰ but three studies of breast milk excretion from women exposed to drinking water with arsenic concentrations of approximately 200 μg/L came to disparate conclusions. Breast milk arsenic concentrations were low in these studies, and only one of them demonstrated a correlation between maternal arsenic concentrations and concentrations in breast milk.^52,67,195 The authors of one of the two negative studies suggest that breast feeding actually protects the infant from arsenic exposure.⁶⁷

Metabolism, by adding methyl groups, occurs primarily in the liver, as well as in the kidneys, testes, and lungs (Fig. 89–3). If the arsenic is pentavalent, approximately 50% to 70% of As⁵⁺ will first be reduced to As³⁺.^51,209,229 This bioactivation step requires the oxidation of glutathione⁵⁸ and can begin within 15 minutes of exposure.²²⁹ S-adenosylmethionine (SAM) is the primary methyl donor. Nonenzymatic methylation is also demonstrated in an in vitro study using human liver cytosol; here, methylcobalamin (methyl B₁₂) was the methyl donor.²⁵⁵ Dietary and vitamin deficiencies, as well as high doses of inorganic arsenic, may diminish the ability to methylate arsenic, and folate supplementation lowers blood arsenic concentrations in a folate-deficient population.^{15,75,76, and 77,93,97,98,176,178,230} However, a study in pregnant Bangladeshi women showed efficient arsenic methylation despite nutritional deficiencies.¹³⁶ Addition of one methyl group produces monomethyl-arsonic acid (MMA⁵⁺); adding a second methyl group produces dimethylarsinic acid (DMA⁵⁺). Production of a trivalent intermediate in this reaction, monomethylarsonous acid (MMA³⁺), is catalyzed by MMA⁵⁺ reductase. In rabbits this is the rate-limiting enzyme in the biotransformation pathway; however, no data exist to confirm a similar role in human metabolism.^227,256 Conversion of MMA⁵⁺ to DMA⁵⁺ is catalyzed by a methyltransferase. Genomic studies have begun to identify gene polymorphisms in these pathways that are associated with variations in arsenic metabolism and toxicity.^3,175

These monomethylation and dimethylation steps were previously thought to detoxify arsenic, but this has been questioned because of the generation of these trivalent intermediates, which are more toxic than the parent compounds.²²⁵ Estimated human LD₅₀ (median lethal dose for 50% of test subjects) doses were reported to be As₂O₃, 1.43 mg/kg; MMA⁵⁺,50 mg/kg; and DMA⁵⁺, 500 mg/kg. However, it is important to note that the doses cited for MMA and DMA apply to arsenic existing in the pentavalent form (As⁵⁺). Studies in animals and cell cultures indicate that MMA³⁺ may be more toxic than As³⁺.^144,173,174 Cytotoxicity studies in human hepatocytes revealed descending toxicity of arsenic and its metabolites as follows: MMA³⁺ > arsenite > arsenate > MMA⁵⁺ = DMA⁵⁺.¹⁷³ Thus, toxicity increases with the formation of MMA³⁺.

There is some evidence that these findings have clinical relevance. In a study from a blackfoot disease–hyperendemic area of Taiwan, lower capacity to methylate inorganic arsenic to DMA⁵⁺ was associated with increased risk of blackfoot disease. The capacity to methylate arsenic to DMA⁵⁺ was measured as the ratio of DMA⁵⁺ to MMA⁵⁺ and the ratio of MMA⁵⁺ to the sum of As³⁺ and As⁵⁺.²¹⁹ In addition, a cohort study found that the odds of premalignant skin lesions increased with increasing urinary MMA⁵⁺ and decreasing urinary DMA⁵⁺.³ They also found that there was an increased risk of skin lesions associated with genetic polymorphisms of glutathione S-transferase and borderline increased risk with polymorphisms of methylenetetrahydrofolate reductase. The authors suggested that the conversion of MMA⁵⁺ to DMA⁵⁺ may be saturable and that arsenic metabolism and toxicity are affected by genetics.³ An additional nested case-controlled study of this cohort confirmed that folate deficiency and DNA hypomethylation were risk factors for skin lesions.¹⁷⁷

Arsenobetaine (AsB) is also well absorbed orally and is excreted unchanged in the urine.²²⁸ Elimination occurs more rapidly than with inorganic arsenic. In a study involving human volunteers, 25% was excreted within 2 to 4 hours, 50% by 20 hours, and 70% to 83.7% after 166 hours. A two-compartment exponential model shows nearly 50% of the AsB eliminated, with a first compartment t_1/2 of 6.9 to 11.0 hours and a second compartment t_1/2 of 75.7 hours.¹¹¹

Inorganic Arsenicals

Toxic manifestations vary, depending on the amount and form, route, and chronicity of arsenic exposure. Other influencing factors include individual variations in methylation and excretion. Larger doses of a potent compound, such as As₂O₃, will rapidly produce manifestations of acute toxicity, whereas chronic ingestion of substantially lower amounts of As⁵⁺ in groundwater will result in different clinical findings over time. Manifestations of subacute toxicity can develop in patients who survive acute poisoning, as well as in patients who are slowly poisoned environmentally.

Acute Toxicity.

GI signs and symptoms of nausea, vomiting, abdominal pain, and diarrhea, which occur 10 minutes to several hours following ingestion, are the earliest manifestations of acute poisoning by the oral route. The diarrhea has been compared to cholera in that it may resemble “rice water.” Severe multisystem illness can ensue with extensive exposure. Cardiovascular signs, ranging from sinus tachycardia and orthostatic hypotension to shock, can develop. Reported cases have mimicked myocardial infarction or systemic inflammatory response syndrome, with intravascular volume depletion, capillary leak, myocardial dysfunction, and diminished systemic vascular resistance.^{16,22,24,85,112,200} Acute encephalopathy can develop and progress over several days, with delirium, coma, and seizures attributed to cerebral edema and microhemorrhages.^71,200 Seizures may be secondary to dysrhythmias, and the underlying cardiac rhythm should be assessed. Seizures apparently secondary to torsade de pointes associated with a prolonged QT interval developed 4 days to 5 weeks after acute arsenic ingestion.^22,83,207 Acute respiratory distress syndrome (ARDS) and respiratory failure, hepatitis, hemolytic anemia, acute kidney injury (AKI), rhabdomyolysis, other ventricular dysrhythmias, and death can occur.^{24,69,88,156,222} Death may occur after suddenly developing bradycardia, followed by asystole.^24,112,141 Fever may develop, misleading the practitioner to diagnose sepsis.^62,112 Hepatitis can occur and may be a result of altered intrahepatic heme metabolism causing an increased synthesis of bilirubin or a result of altered protein transport between hepatocytes.⁶ AKI failure may be secondary to ischemia caused by hypotension, tubular deposition of myoglobin or hemoglobin, renal cortical necrosis, and direct renal tubular toxicity.^{26,80,197,222} Glutathione depletion may be contributory.¹⁰³ Unusual complications include phrenic nerve paralysis, unilateral facial nerve palsy, pancreatitis, pericarditis, and pleuritis.^18,256 Fetal demise has been reported, with toxic arsenic concentrations found in the fetal organs.^24,140

Acutely poisoned patients with less severe illness may experience gastroenteritis and mild hypotension that persist despite antiemetic and intravenous crystalloid therapies. Hospitalization and continued intravenous fluids may be required for several days.¹³² The prolonged character of the GI symptoms is atypical for most viral and bacterial enteric illnesses and should alert the physician to consider arsenic poisoning, especially if there is a history of repetitive GI illnesses. A metallic taste or oropharyngeal irritation, mimicking pharyngitis, can occur.^24,100 GI ulcerative lesions and hemorrhage are reported.^71,85 Toxic erythroderma and exfoliative dermatitis result from a hypersensitivity reaction to arsenic.²¹⁴

In the days and weeks following an acute exposure, prolonged or additional signs and symptoms in the nervous, GI, hematologic, dermatologic, pulmonary, and cardiovascular systems can occur. Encephalopathic findings of headache, confusion, decreased memory, personality change, irritability, hallucinations, delirium, and seizures may develop and persist.^62,74,192 Sixth cranial nerve palsy and bilateral sensorineural hearing loss are reported.^50,83 Peripheral neuropathy typically develops 1 to 3 weeks after acute poisoning, although in one series nine patients developed maximal neuropathy within 24 hours of exposure.^{50,100,132,241} Sensory symptoms develop first, and diminished to absent vibratory sense may be present. Progressive signs and symptoms include numbness, tingling, and formication with physical findings of diminished to absent pain, touch, temperature, and deep-tendon reflexes in a stocking-glove distribution. Superficial touch of the extremities may elicit severe or deep aching pains, a finding that also occurs with thallium poisoning (Chap. 102). Motor weakness may then develop. The most severely affected patients manifest an ascending flaccid paralysis that mimics Guillain-Barré syndrome.^50,100,132 Respiratory findings can include dry cough, crackles, hemoptysis, chest pain, and patchy interstitial infiltrates.^100,172 These findings may be misinterpreted as viral or bronchitic disease. Leukopenia, and less commonly anemia and thrombocytopenia, occur from days to 3 weeks after an acute exposure, but resolve as bone marrow function returns.^108,135

Dermatologic lesions can include patchy alopecia, oral herpetiform lesions, a diffuse pruritic macular rash, and a brawny nonpruritic desquamation (Chap. 18). Diaphoresis and edema of the face and extremities can develop.¹ Mees’ lines (transverse striate leuconychia of the nails) are 1- to 2-mm wide horizontal nail bands that represent disturbed nail matrix keratinization (Fig. 89–4). They are uncommon in arsenic poisoning. A minimum of 30 days after exposure is required for the lines to extend visibly beyond the nail lunulae.^100,248 Contact dermatitis has been reported from topical exposure in an occupational setting. Other possible toxic manifestations of subacute inorganic arsenic toxicity include nephropathy, fatigue, anorexia with weight loss, torsade de pointes, and persistence of GI symptoms.^16,145

Chronic Toxicity.

Malignant and nonmalignant skin changes, hypertension, diabetes mellitus (DM), and peripheral and cerebral vascular disease, as well as lung, bladder, and hepatic malignancies are associated with drinking water containing arsenic that is consumed by study populations.^{47,152,170,180,252} The skin is very susceptible to the toxic effects of arsenic; multiple dermatologic lesions have been reported in populations suffering from hydroarsenicism.^148,252 Alterations in pigmentation occur first, with hyperpigmentation being the most common. Hypopigmentation (“raindrop” pattern) can also occur (Fig. 89–5). Hyperkeratoses typically develop on the palms and soles, but can be diffuse (Fig. 89–6). Squamous and basal cell carcinomas and Bowen’s disease (intraepidermal squamous cell carcinoma) may occur. Bowen’s disease usually proliferates in multiple sites, especially on the trunk, and is noted for developing on sun-protected areas. Latency periods for developing keratoses, Bowen’s disease, and squamous cell carcinoma were 28, 39, and 41 years, respectively, in 17 patients chronically exposed to environmental or medicinal arsenic.^56,247 GI symptoms of nausea, vomiting, and diarrhea are less likely but can occur. Hepatomegaly was present in 120 of 156 patients with hydroarsenicism; liver biopsy in 45 cases revealed a noncirrhotic portal fibrosis in 91.1%.¹⁴⁸ Rodent studies also demonstrate hepatic fibrosis from inorganic arsenic exposure.¹⁹⁶ Portal hypertension and hypersplenism have occurred.^148,196 Hepatic angiosarcomas are linked to arsenic exposure.^48,114,130

Some, but not all, population studies in areas of Bangladesh, Taiwan, and the United States with arsenic-contaminated water show an increased prevalence of DM, pulmonary fibrosis, and other organ system effects.^{39,117,182,183,220} A cross-sectional drinking water study from the United States revealed an odds ratio of 3.58 for prevalence of type 2 DM among those at the 80th percentile, as compared to those at the 20th percentile, despite a median total arsenic concentration of only 7.1 ppb.^129,160 However, a cross-sectional study in Bangladesh did not find a relationship between arsenic exposure and DM.³⁹ Animal studies demonstrate that arsenic can decrease insulin-mediated uptake of glucose by cells and can also disrupt insulin transcription factor signal transduction.^169,236 In a study from West Bengal, restrictive lung disease was reported in 9 of 17 patients, and a restrictive plus obstructive pattern occurred in another 7 cases.¹⁴⁸ Lung disease has also been noted in other populations.⁹⁰ Proposed mechanisms include arsenic-induced inflammation and oxidative stress.¹⁶⁶ Aplastic anemia and agranulocytosis are documented in patients exposed to arsenic.⁶² A dose-response relationship between arsenic exposure and vascular disease is reported in several populations.²³⁸ After adjusting for age, sex, hypertension, DM, cigarette smoking, and alcohol consumption, a significant relationship was observed with cerebrovascular disease in a region of Taiwan.⁴⁷ Blackfoot disease, an obliterative arterial disease of the lower extremities, occurring in Taiwan, is linked to chronic arsenic exposure,^35,218 as is ischemic heart disease.³³ The incidence of Raynaud’s phenomenon and vasospasm was reported to be increased in smelter workers exposed to arsenic, compared with a control group.¹²⁸ Encephalopathy and peripheral neuropathy are the neurologic manifestations most commonly reported.^21,99 Electromyographic studies of 33 patients with chronic ingestion of arsenic-contaminated water revealed 10 patients with findings consistent with sensory neuropathy. The minimum duration of exposure was 2 years. Interestingly, three of these patients consumed water with an arsenic concentration that only slightly exceeded the contaminant concentration of 50 ppb previously permissible in the United States.¹⁰²

Arsenic is classified as a definite carcinogen by the International Agency for Research on Cancer (IARC, Group 1) and the National Toxicology Program (NTP). Cancers known to develop include lung, skin, and bladder.^{12,49,107,195,204} Transitional cell bladder carcinoma was the most common type in one large epidemiologic study.⁴⁶ However, the exposure threshold of concern remains controversial.¹⁵¹ A critical literature review of animal and human studies found that exposure to environmental arsenic was unlikely to cause reproductive or developmental toxicity.⁵⁹ However, a more recent rodent study revealed fetal growth retardation and neurotoxicity at doses relevant to human exposure and in the absence of maternal toxicity.²³⁷ More concerning, two recent drinking water cohort studies from Bangladesh showed small but statistically significant increases in birth defects and fetal loss.^125,182,226 In addition to possibly increasing the risk of birth defects, there is also cohort and cross-sectional evidence that in utero or early childhood exposure may be associated with persistent neurocognitive effects in children.^{31,39,54,94,95,117,217,234,239,240} Finally, there is evidence that in utero or early childhood exposure to arsenic in drinking water increases the risk of malignant and nonmalignant lung diseases in young adults.²⁰⁴ In summary, there is accumulating evidence of persistent adverse effects from in utero or early childhood exposure, but additional prospective studies are needed to confirm these findings by decreasing the effects of confounding and bias that may explain the results.

Many of the questions regarding the chronic health effects of exposure to arsenic in drinking water are currently being investigated in the Health Effects of Arsenic Longitudinal Study (HEALS). This study was designed to evaluate the health effects of a full range of drinking water arsenic exposures, including mortality, premalignant and malignant skin tumors, pregnancy outcomes, and children’s cognitive development.⁵

This study is a prospective cohort study in Araihazar, Bangladesh. Participants were between the ages of 18 and 75 years and married, although both members of a couple were not required to enroll. A total of 11,764 subjects enrolled, 6704 women and 5042 men. The participation rate in the initial enrollment was 97.5% of those approached.⁵ Of those who agreed to participate, 98% completed an extensive questionnaire that included demographic and lifestyle components and a validated food-frequency questionnaire. They also participated in a clinical examination with an extensive skin evaluation. More than 90% of this group also provided blood and spot urine arsenic samples.⁵

Approximately one third of the participants consumed water in each of three groups: greater than 100 μg/L, 25 to 100 μg/L, and less than 25 μg/L. Average urinary concentrations of arsenic were approximately 140 μg/L.

Many studies from this cohort have been published. Studies of persons with arsenic-induced skin lesions have shown increasing risk of disease as exposure increases.^4,13 Modification of risk was noted in relationship to nutritional status, sunlight exposure, smoking, and some occupational exposures such as fertilizers and pesticides.^41,42,153 A dose-response relationship was also found for other health effects, including total mortality,¹⁴ cardiovascular disease,⁴⁰ respiratory symptoms,¹⁶⁷ proteinuria,⁴³ oral cavity lesions,²¹⁰ and neurologic effects.^91,168 Biannual follow-up of this cohort continues.

Adverse Drug Effects: Arsenic Trioxide

The most common adverse effects are dermatologic (skin dryness, pigmentary changes, maculopapular eruptions with or without pruritus); GI (nausea, vomiting, anorexia, diarrhea, and dyspepsia); hematologic (leukemoid reactions); hepatic (elevation of aminotransferase concentrations typically less than or equal to 10 times the upper limit of normal values, with a reported incidence of 20% with low-dose and 31.9% with conventional-dose therapy²⁰¹); cardiac (prolonged QT interval in 40%–63% of patients, first-degree atrioventricular block, ventricular ectopy, monomorphic nonsustained ventricular tachycardia, torsade de pointes, asystole, and death);^{194,201,205,224,245} facial edema; and neurologic (paresthesias, peripheral neuropathy, and headache). All of these effects occurred more commonly in one case series with conventional-dose therapy (0.16 mg/kg/d) when compared to low-dose therapy. The majority of patients are treated symptomatically without discontinuing As₂O₃ treatment. Leukemoid reactions, defined as white blood cell counts greater than 50 × 10⁹/L, develop in nearly 50% of patients between 14 and 42 days of beginning treatment. Such patients are at risk for intracerebral hemorrhage or infarction and for the APML syndrome. This syndrome is similar to the differentiation syndrome (DS), which was formerly known as the retinoic acid syndrome.¹⁵⁵ The remission induction treatment phase is the period of greatest risk.²⁰² Common clinical findings in this syndrome include pulmonary interstitial infiltrates and/or pleural effusions, dyspnea, tachypnea, fluid retention, myalgias, arthralgias, fever, and weight gain; approximately 20% to 25% of patients treated with arsenic trioxide will develop one or more signs or symptoms of this syndrome.^{146,159,194,201,202}

Although a theoretical concern, there is currently no evidence of increased risk of secondary malignancies in treated patients. Continued close follow-up will be necessary to evaluate whether secondary malignancy risk will increase over time.⁶⁵

Timing of testing for arsenic must be correlated with the clinical course of the patient and whether the poisoning is acute, subacute, chronic, or remote with residual clinical effects. To properly interpret laboratory measurements, confounding factors, such as food-derived organic arsenicals or accumulated arsenic (DMA and arsenobetaine) in patients with chronic kidney disease, must be considered.^55,260,261 Failure to understand potential confounders, as well as the time course of arsenic metabolism, clearance, and effect on laboratory parameters, can cause erroneous assessment of possible arsenic poisoning.

Urine and Blood

Diagnosis ultimately depends on finding an elevated urinary arsenic concentration. In an emergency, a spot urine may be sent prior to beginning chelation therapy. A markedly elevated arsenic concentration verifies the diagnosis in a patient with characteristic history and clinical findings, but a low concentration does not exclude arsenic toxicity.²³⁵ In nine acutely symptomatic patients, initial spot urine arsenic concentrations ranged from 192 to 198,450 μg/L.¹¹⁶ Definitive diagnosis of arsenic exposure hinges on finding a 24-hour urinary concentration equal to or greater than 50 μg/L, 100 μg/g creatinine, or 100 μg total arsenic. A study on arsenic exposure from drinking water showed excellent correlations between spot and 24-hour urine arsenic concentrations. There are not enough data to determine if this relationship holds true in acutely poisoned patients, so a 24-hour collection is still preferred.³² Challenge testing with dimercaptopropane sulfonate (DMPS) has been performed in individuals exposed to arsenic in drinking water and clearly increases arsenic excretion; however, it also alters the percentages of the arsenic species recovered compared with controls and has not been correlated with clinical effects.¹¹ All urine should be collected in metal-free polyethylene containers; acid-rinsed containers are not recommended since the acid alters the arsenic species.⁶⁸ If testing is performed by an outside reference laboratory, specimens from acutely ill patients should be sent via express transportation with a request for a rapid result.

When interpreting slightly elevated urinary arsenic concentrations, laboratory findings must also be correlated with the history and clinical findings, because seafood ingestion is reported to transiently elevate urinary total arsenic excretion up to 1700 μg/L.¹² When seafood arsenic is a consideration, speciation of arsenic can be accomplished by high-performance liquid chromatography (HPLC) separation, followed by inductively coupled plasma-mass spectrometry (ICPMS), HPLC via ion-pair chromatography coupled with hydride-generation atomic-fluorescence spectrometry (HGAFS), or by hydride generation coupled with cold-trap gas chromatography-atomic absorption spectrometry. These techniques separate AsB, As³⁺, As⁵⁺, MMA, and DMA.⁶⁸ Arsenobetaine can also be directly measured by silica-based cation-exchange separation, followed by atomic absorption spectrometry.¹⁶² Two other methods, selective hydride-generation atomic-absorption spectrometry (HGAAS) and resin-based ion-exchange chromatography, do not directly measure AsB; instead, they indirectly derive this value by subtracting the sum of all measured arsenic species from the total arsenic concentration.¹⁶² If arsenic speciation cannot be done, the patient can be retested after a one-week abstinence from fish, shellfish, and algae food products.

Conditions under which urine is stored can affect total arsenic recovery, as well as proportionality of the species. The various arsenic species—arsenate (As⁵⁺), arsenite (As³⁺), MMA, DMA, and AsB—remain stable for 2 months in urine stored without preservatives at either –4°F (–20°C; freezer) or 39.2°F (4°C; refrigerator); AsB is stable for 8 months under these conditions. Storage for longer than 2 months can alter the recovery of various species. Addition of 0.1% hydrochloric acid (HCl) facilitates reduction of arsenate to arsenite and also decreases MMA and DMA concentrations. Acid-washed collection containers should not be used if measurement of the various arsenic species is planned. Total arsenic recovery can be diminished by any of the following: specimen storage for greater than 2 months, acidification, or testing using HPLC-ICPMS and HPLC-HGAFS, since all these methods usually require that the samples be filtered prior to undergoing HPLC separation.⁶⁸

Diagnostic evaluation of chronic toxicity should include laboratory parameters that may become abnormal within days to weeks following an acute exposure. Tests should include a complete blood count, renal and liver function tests, urinalysis, and 24-hour urinary arsenic determinations. Complete blood count findings can include a normocytic, normochromic, or megaloblastic anemia; an initial leukocytosis followed by development of leukopenia, with neutrophils depressed more than lymphocytes, and a relative eosinophilia; thrombocytopenia; and a rapidly declining hemoglobin, indicative of hemolysis or a GI hemorrhage.¹²⁷ Basophilic stippling of RBCs can be seen; this can occur in other toxic and clinical disorders. Karyorrhexis, a rupture of the RBC cell nucleus with chromatin disintegration into granules that are extruded from the cell, and dyserythropoiesis are reported in both lead- and arsenic-toxic patients. Both findings are caused by arsenic-induced inhibition of DNA synthesis and damage to the nuclear envelope.⁶⁴ The karyorrhexis can occur within 4 days and resolve by 2 weeks after poisoning, and may be an early indication of arsenic toxicity.¹²⁷ Elevated serum creatinine, aminotransferases, and bilirubin, as well as depressed haptoglobin concentrations, may develop. Urinalysis may reveal proteinuria, hematuria, and pyuria. Cerebrospinal fluid examination in patients with CNS findings can be normal or exhibit mild protein concentration elevation, measured at 26.5 mg/dL in one case.¹⁰⁰ Urinary arsenic excretion in subacute and chronic cases varies inversely with the postexposure time period, but low-concentration excretion can continue for months after exposure. In a study of 41 cases of arsenic-induced peripheral neuropathy, most patients with a neuropathy of 4 to 8 weeks duration had total 24-hour urinary arsenic measurements of 100 to 400 μg.¹⁰⁰

Hair and Nail Testing

In cases of suspected arsenic toxicity, in which the urinary arsenic measurements fall to less than toxic concentrations, analysis of hair and nails may yield the diagnosis. Arsenic can be detected in the proximal portions of hair within 30 hours of ingestion.²⁵³ Inorganic arsenic is the form best absorbed by these tissues and the form most commonly found in human poisoning cases; small amounts of methylated metabolites may also be detected.¹⁸¹ Arsenobetaine has not been found in hair and tissues in human and animal studies.^250,251 Hair grows at rates varying from 0.7 to 3.6 cm per month, with a mean rate of 1 cm per month.²⁴² The Society of Hair Testing has made the following recommendations for collection of hair specimens, although they are only validated for testing drugs of abuse: (a) collect approximately 200 mg of hair from the posterior vertex region of the scalp using scissors to cut as close to the scalp as possible, and (b) tie the hairs together, wrap in aluminum foil to protect from environmental contamination, and store at room temperature.²⁴² Nails grow approximately 0.1 mm per day. Total replacement of a fingernail requires 3 to 4 months, whereas toenails require 6 to 9 months of growth. These facts, plus the frequency of hair cutting, should be considered when estimating the usefulness of measuring arsenic levels in these tissues. The normal values of the testing laboratory should be used to determine whether arsenic concentrations are elevated. In cases of remote toxicity, hair and nail arsenic measurements may or may not be elevated, depending on the time elapsed since exposure. Sequential hair analysis to assess the time(s) of exposure can be performed by solid sampling graphite furnace atomic absorption spectrophotometry or by x-ray fluorescence spectrometry.^118,215,216

Other Tests

Abdominal radiographs might demonstrate radiopaque material in the GI tract soon after an ingestion.^{2,45,85,86,101} However, even after an acute ingestion, the absence of radiopaque materials on abdominal radiographs is reported.⁵³ The incidence of positive radiographs after an ingestion is unknown, and a negative radiograph should not eliminate arsenic as a diagnostic consideration. Electrocardiographic changes reported include QRS widening, QT prolongation, ST-segment depression, T-wave flattening, ventricular premature contractions, nonsustained monomorphic ventricular tachycardia, and torsade de pointes.^{20,164,205,224} Nerve conduction studies (NCS) can confirm or diagnose clinical or subclinical axonopathy. Both the sensory nerve action potential (SNAP) and the motor compound muscle action potential (CMAP) measure the number of axons that are available to conduct impulses. Since the sensory studies are more sensitive than motor studies in detecting axonal degeneration and demyelination, decreased SNAP measurements better indicate subclinical neuropathy. In motor nerve studies, the amplitude (height of the CMAP) is a more sensitive measure of the number of axons that can conduct impulses than is the conduction velocity; this can be explained by the pattern of axonal destruction as opposed to myelin injury (which mainly affects conduction velocity). Nerve biopsies have confirmed disintegration of both axons and myelin in patients with arsenic-induced peripheral neuropathy; the axonal loss begins distally in the lower extremities and is initially scattered. Thus, conduction along the remaining functional axons can be sufficient to produce normal or only slightly decreased conduction measurements on NCS.^{82,100,119,132,158,163}

General

Acute arsenical toxicity is life threatening and mandates aggressive treatment. Advanced life support monitoring and therapies should be initiated when necessary, but with a few caveats. Careful attention to fluid balance is important because cerebral and pulmonary edema may be present. Xenobiotics that prolong the QT interval, such as the class IA, class IC, and class III antidysrhythmics, should be avoided whenever possible (Chaps. 16 and 64). Potassium, magnesium, and calcium concentrations should be maintained within normal range to avoid exacerbating a prolonged QT interval. Glucose concentrations and glycogen stores should be maintained parenterally with dextrose and hyperalimentation solutions or with enteral feedings, in view of their beneficial effects in experimental models of arsenic poisoning.^{138,187,188,211}

GI decontamination of patients acutely poisoned with arsenic is controversial. Arsenic poorly adsorbs to activated charcoal, cholestyramine, and bentonite.¹⁸⁵ Moreover, significantly poisoned patients usually have nausea and vomiting and may have altered mental status, which make activated charcoal administration difficult. Despite these concerns, activated charcoal in conjunction with airway protection if necessary is recommended because of the relatively low likelihood of harming the patient and the hope that preventing even a small amount of absorption might prevent or lessen the potentially disastrous consequences of arsenic poisoning. If radiopaque material is visualized in the GI tract, whole bowel irrigation can be administered until the radiopaque material is no longer visualized on repeat abdominal radiograph. Continuing nasogastric suction may be important in removing arsenic resecreted in the gastric or biliary tract. Arsenite was still detectable in the gastric aspirate in three patients 5 to 7 days following an ingestion.¹⁴³ There is no clinical experience with the use of N-acetylcysteine to increase glutathione concentrations, although an animal model suggested a protective effect.¹⁸⁴

In cases of chronic toxicity, patients should be removed from the arsenic source, and gastric decontamination should be performed if there is evidence of arsenic in the GI tract. Arsenic can be readily removed from skin with soap, water, and vigorous scrubbing. In this situation, when homicidal intent is suspected, all hospital visitors should be closely monitored, and outside nutritional products should be forbidden.

Chelation Therapy

Chelators.

Dimercaprol (BAL) and 2,3-dimercaptosuccinic acid ­(succimer) are the two chelators available in the United States. A third drug, DMPS, is distributed by Heyl, a German pharmaceutical company, as ­Dimaval, but it is not approved or marketed in the United States (Antidotes in Depth: A25 and A26). All contain vicinal dithiol moieties that bind arsenic to form stable 1,2,5-arsadithiolanes (Fig. 89–7), and all are most effective when administered in doses equimolar to the arsenic burden.¹⁵⁷ Dosing regimens and adverse effects are listed in Table 89–3.

The decision to initiate chelation therapy should depend on the clinical condition of the patient as well as the laboratory results for arsenic in urine, hair, or nails. A severely ill patient with known or suspected acute arsenic poisoning should be chelated immediately, prior to laboratory confirmation. In the United States, BAL remains the initial chelating drug for acute arsenical toxicity.¹⁵⁷ In a series of 33 patients who had coma, seizures, or both, 24 patients were treated with BAL within 6 hours (mean, 1 hour) and 75% survived, compared with a survival rate of 45% of nine patients who were treated later (range, 9–72 hours; mean, 30 hours).⁶² Cases of subacute and chronic toxicity can await rapid laboratory confirmation prior to beginning chelation, unless the clinical condition deteriorates.

In a cellular study of glucose uptake impaired by a lipophilic arsenical, BAL was superior to succimer and DMPS in restoring cellular equilibrium.¹⁵⁷ A human case series found increased survival with early use of BAL and improvement in encephalopathy within 24 hours of initiating therapy.⁶² However, other acute cases treated promptly with BAL developed peripheral neuropathy.¹³² In a study of subacute cases with peripheral neuropathy, BAL accelerated neurologic recovery but did not affect the overall recovery rate.⁵⁰ Despite starting BAL therapy 8 hours postexposure, a man who had ingested 2.15 g of arsenic developed severe toxicity and neurologic deficits.⁷⁰ Most concerning are the animal experiments indicating that BAL shifts arsenic into the brain and testes, two organs that have blood–organ barriers susceptible to this lipophilic drug.^10,104,121 It is clear that BAL has limitations, and that a safer, more effective intracellular/extracellular parenteral chelator is needed.

Succimer is an oral hydrophilic analog of BAL and is the chelator of choice for subacute and chronic toxicity. It has proven effective in animal studies and in reported human cases.^{10,120,134,142,203} In mice exposed to sodium arsenite, succimer was more effective than either DMPS or BAL in decreasing lethality and more potent than BAL in restoring activity in the pyruvate dehydrogenase complex.¹⁰ It is equal or superior to BAL in speeding arsenic elimination.¹⁵⁷ Liver function tests and essential metal concentrations should be monitored in patients requiring prolonged therapy.^73,87

DMPS is also a water-soluble analog of BAL. It is not approved for use in the United States. It can be administered by the oral, intravenous, and intramuscular routes. It is eliminated from the body more slowly than succimer and has the advantage of intracellular as well as extracellular distribution.⁷ It predominantly binds MMA³⁺ and possibly removes the MMA³⁺ from endogenous ligands. The DMPS–MMA³⁺ complex is eliminated in the urine.^9,11,84 It may also work by synergistically increasing the nonenzymatic methylation of As³⁺.²⁵⁵ Two brothers ingested nearly pure arsenic trioxide (1 and 4 g each) and were treated with intravenous and oral DMPS. The brother who ingested 4 g developed hypotension, AKI, respiratory insufficiency, and asystolic cardiac arrest. DMPS was started 32 hours postingestion, and the patient survived with normal renal function and no neurologic dysfunction. His sibling had a milder course; DMPS was started 48 hours postingestion, and there were no neurologic sequelae on follow-up examination.¹⁵⁶ DMPS significantly increased biliary excretion of arsenic in a guinea pig model but did not increase fecal excretion. The latter is most likely a result of enterohepatic recirculation of the DMPS–As complex.¹⁸⁵ However, in another guinea pig model, the addition of oral cholestyramine to either DMPS or DMSA but not to BAL increased fecal arsenic excretion.¹⁵⁷

d-Penicillamine has not demonstrated efficacy in chelating or reversing the biochemical lesions of arsenic and should not be used. Its previous advantage of oral administration is no longer relevant with the availability of succimer.

Because of the limitations of currently available chelators, research is ongoing to find better chelators to treat arsenic toxicity. For example, some analogs of succimer, especially its monoisoamyl ester, have increased intracellular penetration relative to the parent compound and increase survival in arsenic-poisoned rats.^72,113 In addition to improved chelators, other treatments for arsenic toxicity are being investigated. Some rodent studies have suggested that certain micronutrients, such as zinc or selenium, can decrease arsenic toxicity.⁷² However, early findings from the HEALS cohort are mixed. A cross-sectional substudy from this group revealed an inverse relationship between the severity of skin lesions and dietary intake of folate; pyridoxine; riboflavin; and vitamins A, C, and E.²⁵⁴ In contrast, another study from the same cohort did not find a statistically significant relationship between the severity of skin lesions and supplementation with vitamin E, selenium, or both.²³³ Until more data are available, nutritional supplementation, in the absence of dietary deficiency, remains controversial.

Hemodialysis.

Hemodialysis removes negligible amounts of arsenic, with or without concomitant BAL therapy, and is not indicated in patients with normal kidney function.^23,96,147 In patients with AKI, hemodialysis clearance rates have ranged from 76 to 87.5 mL/min, with or without concomitant BAL therapy.²³² In two acutely toxic patients with AKI, total arsenic removed during a 4 hour dialysis measured 4.68 mg in one and 3.36 mg in the other. Concomitant 24 hour urinary arsenic excretions were 3.12 mg and 2.03 mg, respectively. When renal function returned, however, the 24 hour urinary excretion of arsenic far exceeded that recovered with dialysis, with reported amounts of 18.99 mg in the first patient and 75 mg in the second patient.²³² There are no published rigorous data regarding hemodialysis removal of a water-soluble complex such as DMPS–As.¹²³

• Environmental contamination of water sources has become a major health problem in many countries, including the United States.

• Arsenicals produce multisystem toxicity by a variety of pathophysiologic mechanisms.

• A thorough understanding of inorganic arsenic metabolism and excretion as well as the different clinical manifestations of acute, subacute, and chronic toxicity are necessary to avoid misdiagnosis.

• Chelation therapy with BAL in the United States, or with DMPS elsewhere, if available, should be started immediately in the severely ill patient.

• Treatment can await laboratory results for patients with subacute or chronic toxicity, unless clinical deterioration intervenes.

Acknowledgment

Marsha D. Ford, MD, contributed to this chapter in previous editions.

References