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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.
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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
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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
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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
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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
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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
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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
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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.
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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
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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
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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.
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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.
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Adverse Drug Effects: Arsenic Trioxide
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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
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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