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ARSENIC
TOXICITY
Environmental Alert
Except in the electronics industry, commercial use of arsenic is declining. Skin lesions, peripheral neuropathy, and anemia are hallmarks of chronic arsenic ingestion. Arsenic is strongly associated with lung and skin cancer in humans, and may cause other internal cancers as well.
Case Studies in
Environmental Medicine
Course: SS
Revision Date: October 2000
Original Date: June 1990
Expiration Date: October 30, 2006
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
Agency for Toxic Substances and Disease Registry Division of Health Education and Promotion
This monograph is one in a series of self-instructional publications designed to increase the primary care provider’s knowledge of hazardous substances in the environment and to aid in the evaluation of potentially exposed patients. This course is also available on the ATSDR Web site, www.atsdr.cdc. gov/HEC/CSEM/. See page 3 for more information about continuing medical education credits, continuing nursing education units, and continuing education units.
Table of Contents
Tables and Figures Table 1. Standards and Regulations for Inorganic Arsenic ...................... 25
ATSDR/DHEP Revision Content Experts: Kim Gehle, MD, MPH; Deanna Harkins, MD, MPH; Darlene Johnson, RN, BSN, MA; Lourdes Rosales-Guevara, MD ATSDR/DHEP Revision Planners: Diane Dennis-Flagler, MPH; Patricia Drehobl, RN, BSN (CDC/ PHPPO); Kim Gehle, MD, MPH; Darlene Johnson, RN, BSN, MA; Ralph O’Connor Jr., PhD Revision Edited By: Kathleen Kreiss, MD; Pamela S. Wigington Original Contributor: Michael Kosnett, MD, MPH Original Peer Reviewers: Charles Becker, MD; Jonathan Borak, MD; Joseph Cannella, MD; Robert Fried, MD; Bernard Goldstein, MD; Alan Hall, MD; Richard J. Jackson, MD, MPH; Jonathan Rodnick, MD; Robert Wheater, MS; Brian Wummer, MD
Disclaimer The state of knowledge regarding the treatment of patients potentially exposed to hazardous substances in the environment is constantly evolving and is often uncertain. In this monograph, ATSDR has made diligent effort to ensure the accuracy and currency of the information presented, but makes no claim that the document comprehensively addresses all possible situations related to this substance. This monograph is intended as an additional resource for physicians and other health professionals in assessing the condition and managing the treatment of patients potentially exposed to hazardous substances. It is not, however, a substitute for the professional judgment of a health care provider. The document must be interpreted in light of specific information regarding the patient and in conjunction with other sources of authority. Use of trade names and commer- cial sources is for identification only and does not imply endorsement by the Agency for Toxic Substances and Disease Registry or the U.S. Department of Health and Human Services. ATSDR Publication No.: ATSDR-HE-CS-2002-
Case Study ............................................................................................. 5
Who’s At Risk ........................................................................................ 6
Exposure Pathways ................................................................................ 7
Biologic Fate .......................................................................................... 9
Physiologic Effects ................................................................................ 11
Clinical Evaluation ................................................................................. 16
Treatment and Management .................................................................. 20
Standards and Regulations .................................................................... 25
References ........................................................................................... 26
Answers to Pretest and Challenge Questions ......................................... 30
Additional Sources of Information ......................................................... 32
Evaluation Questionnaire and Posttest, Course Number SS3060 ........... 33
Answer Sheet, Course Number SS3060 ............................................... 39
Each content expert for this case study indicated no conflict of interest to disclose with the case study subject matter.
The questionnaire and posttest must be completed and returned electronically, by fax, or by mail for eligibility to receive continuing education credit.
Instructions for Completing CSEM Online
- Read this CSEM, Arsenic Toxicity ; all answers are in the text.
- Link to the MMWR/ATSDR Continuing Education General Information page (www.cdc.gov/atsdr/index.html).
- Once you access this page, select the Continuing Education Opportunities link.
- Once you access the MMWR/ATSDR site online system, select the electronic file and/or register and test for a particular ATSDR course. a. Under the heading “Register and Take Exam,” click on the test type desired. b. If you have registered in this system before, please use the same login and password. This will ensure an accurate transcript. c. If you have not previously registered in this system, please provide the registration information requested. This allows accurate tracking for credit purposes. Please review the CDC Privacy Notice (www.cdc.gov/ privacy.htm). d. Once you have logged in/registered, select the test and take the posttest.
- Answer the questions presented. To receive continuing education credit, you must answer all of the questions. Some questions have more than one answer. Questions with more than one answer will instruct you to “indicate all that are true.”
- Complete the course evaluation and posttest no later than October 29, 2006.
- You will be able to immediately print your continuing education certificate from your personal transcript.
Instructions for Completing CSEM on Paper
- Read this CSEM, Arsenic Toxicity ; all answers are in the text.
- Complete the evaluation questionnaire and posttest, including your name, mailing address, phone number, and e-mail address, if available.
- Circle your answers to the questions. To receive your continuing education credit, you must answer all of the questions.
- Sign and date the posttest.
- Return the evaluation questionnaire and posttest, no later than October 1, 2006 , to CDC by mail or fax: Mail or Fax Continuing Education Coordinator 404-498- Division of Health Education and ATTN: Continuing Education Coordinator Promotion, ATSDR 1600 Clifton Road, NE (MS E-33) Atlanta, GA 30333
- You will receive an award certificate within 90 days of submitting your credit forms. No fees are charged for participating in this continuing education activity.
Case Study
A fair-skinned, 35-year-old male is referred to your clinic for evaluation. His symptoms began approximately 3 months ago, with his chief complaint being insidious onset of numbness and tingling in his toes and fingertips, progressing slowly in the ensuing weeks to involve the feet and hands in a symmetric “stocking-glove” fashion. In the past 2 to 3 weeks, the tingling has taken on a progressively painful, burning quality, and he has noted weakness when gripping tools. A review of systems (ROS) reveals no ataxia, dysphagia, visual symptoms, or bowel or bladder incontinence, and the patient has not complained of headaches, back, neck pain, or confusion.
The patient’s past medical history is remarkable for a flulike illness that occurred approximately 4 months ago and was characterized by 3 to 4 days of fever, cough, diarrhea, and myalgias, which resolved spontaneously.
Further questioning regarding the patient’s social history reveals that he has been a carpenter since completing high school 17 years ago. For the last 10 years, he has lived in a rural, wooded area in a home he built. Approximately 10 months ago he married, and moved with his wife, an elementary school teacher, into a newly built home on an adjacent parcel of land. The patient consumes one to two alcoholic drinks a week, and quit smoking two years ago, but has a history of smoking approximately 15 packs a year. He takes one multivitamin a day, but no prescription medications. Family history is unremarkable; his wife, parents, and two younger brothers are in good health.
The physical exam demonstrates vital signs, as well as head, eyes, ears, nose, and throat (HEENT), to be within normal limits. Respiratory, cardiovascular, and abdominal signs are also normal to auscultation and palpation, and there is no hepatosplenomegaly. Joints show full range of motion (FROM), with no erythema or swelling. There is no lymphadenopathy.
Neurologic examination reveals diminished proprioception in the hands and feet, with a hyperesthetic response to pinprick sensation on the soles. Motor bulk and tone are normal, but there is slight bilateral muscular weakness in dorsiflexors of the toes and ankles, wrist extensors, and hand intrinsics. Reflexes are absent at the ankles and 1+ at the biceps and knees. Coordination and cranial nerve function are within normal limits. A dermatologic examination reveals brown patches of hyperpigmentation, with scattered overlying pale spots in and around the axillae, groin, nipples, and neck. The palms and soles show multiple hyperkeratotic cornlike elevations, 4 to 10 millimeters (mm) in diameter. Three irregularly shaped, sharply demarcated, erythematous, scaly plaques, measuring 2 to 3 centimeters (cm), are noted on the patient’s torso. The remainder of the physical examination is normal.
A 35-year-old carpenter has peripheral neuropathy and skin lesions
of arsenic have shown decreased methylating capacity, which has led to increased deposits of arsenic in liver, lung, and other organ sites, and, presumably, increased susceptibility to arsenic toxicity.
Arsenic can cross the placenta, exposing the fetus. Significant levels of arsenic were found in an infant born 4 days after the mother ingested arsenic in a suicide attempt. Increased incidence of spontaneous abortions, infant congenital malformations, and decreased birth weights have been reported among women and their offspring living near a copper smelter in Sweden. It is not clear that these events can be ascribed solely to arsenic, since other chemicals (including lead, cadmium, and sulfur dioxide) were also present; however, teratogenic effects have been reported in arsenic-exposed animals, and chromosomal damage has been found in arsenic-exposed human leukocyte cultures.
Exposure Pathways
Arsenic is ubiquitous in the environment. It is released into the air by volcanoes, through weathering of arsenic-containing minerals and ores, and by commercial or industrial processes. In industry, arsenic is a by-product of the smelting process for many metal ores such as lead, gold, zinc, cobalt, and nickel. Other potential sources of arsenic exposure are
Natural sources: arsenic-containing mineral ores and groundwater (especially near geothermal activity). Commercial products: wood preservatives, insecticides, herbicides (weed killers and defoliants), fungicides, cotton desiccants, cattle and sheep dips, paints and pigments, antifouling paints, leaded gasoline, and fire salts (multicolored flame). Food: wine (grapes sprayed with arsenic-containing pesticides), tobacco (plants sprayed with arsenic-containing pesticides), and seafood (especially bivalves, certain cold water and bottom-feeding finfish, and seaweed). Industrial processes: purifying industrial gases (removal of sulfur), burning fossil fuels, burning wood treated with arsenic preservatives, electronics manufacturing (microwave devices, lasers, light-emitting diodes, photoelectric cells, and semiconductor devices), hardening metal alloys, preserving animal hides, bronze plating, and clarifying glass and ceramics. Medicinals: Fowler’s solution (potassium arsenite), antiparasitic drugs (carbasone), Donovan’s solution, folk remedies (“Asiatic pill,” kushtay , yellow root), kelp-containing health foods, some naturopathic remedies.
Environmental sources of arsenic exposure include food, water, soil, and air.
Arsenic can cross the placenta, increasing the likelihood of exposure to the fetus.
Arsenic exists in three common valence states: As(0) (metalloid arsenic, 0 oxidation state), As(III) (trivalent state, such as arsenites), and As(V) (pentavalent state, such as arsenates). Arsenic-containing compounds vary in toxicity to mammals according to valence state, form (inorganic or organic), physical state (gas, solution, or powder) and factors such as solubility, particle size, rates of absorption and elimination, and presence of impurities. Inorganic arsenic is generally more toxic than organic arsenic. However, animal studies have shown that methyl and phenyl arsenates can produce health effects similar to those produced by inorganic arsenic. The toxicity of As(III) is several times greater than that of As(V), due to greater cellular uptake. At equivalent intracellular levels, As(III) and As(V) compounds are equipotent. Metalloid arsenic is generally regarded as nonpoisonous due to its insolubility in water and body fluids. Arsine gas (AsH 3 ), used commercially in the microelectronics industry and encountered accidentally in metallurgical and mining processes, produces a clinical syndrome which is very different from syndromes produced by other arsenic compounds, and is the most toxic arsenical.
Until the 1940s, arsenicals (Salvarsan and Fowler’s solution) were widely used in the treatment of various diseases such as syphilis and psoriasis. Arsenicals are still used as antiparasitic agents in veterinary medicine, and, in some countries, they are occasionally used to treat trypanosomiasis and amebiasis in humans. Arsenic is also found in some homeopathic and naturopathic preparations, and in folk remedies such as kushtay, a tonic used in Asian cultures to cure various sexual disorders.
Arsenic production has greatly decreased in the United States, but imports have increased steadily and substantially in recent years. Currently, the principal use of arsenic is in products used for wood preservation. Most of the rest is used in the production of insecticides, herbicides, algicides, and growth stimulants for plants and animals. Gallium arsenide (GaAs) is used in integral components of discrete microwave devices, lasers, light-emitting diodes, photoelectric chemical cells, and semiconductor devices. The use of arsine gas (AsH 3 ) as a dopant in the production of semiconductors is also expected to increase, although substitutes of lower toxicity such as tributylarsine have recently been used. A source of arsine exposure is accidental release during manufacture, transport, or use of the gas. More often, however, arsine forms unexpectedly when acid or other reducing substances are added to arsenic-containing compounds, such as metals in which arsenic is a low-level contaminant.
In the general population, the main route of arsenic exposure is via ingestion of arsenic-containing food. Intake from air, soil, and water is usually much smaller. It has been estimated that the average daily dietary intake of arsenic by adults in the United States is 11 to 14 milligrams per day. Meat, fish, and poultry account for 80% of dietary arsenic intake. Fish, seafood, and algae
The relative toxicity of an arsenical depends primarily on inorganic or organic form, valence state, solubility, physical state and purity, and rates of absorption and elimination.
U.S. arsenic production has decreased, but imports have increased.
occupational accidents where either arsenic trichloride or arsenic acid was splashed on workers’ skin. There are no quantitative studies of this route of exposure, but it is of minor importance compared to other routes of exposure such as inhalation and ingestion.
Airborne arsenic in the workplace is generally in the form of arsenic trioxide. Its particle size determines whether arsenic will reach the lower respiratory tract or be deposited in the upper airways and be swallowed after mucociliary clearance. Autopsies performed on retired smelter workers show that insoluble arsenic-containing particles may remain in the lungs for years.
After absorption through the lungs or gastrointestinal tract, arsenic initially accumulates in the liver, spleen, kidney, lungs, and gastrointestinal tract. Clearance from these tissues, however, is rapid. Two to four weeks after exposure ceases, most of the arsenic remaining in the body is found in keratin-rich tissues such as skin, hair, and nails, and to a lesser extent, in bones and teeth.
Oxidation-reduction reactions result in some interconversion of As(V) and As(III) in vivo, thus blurring the distinction between these two groups of inorganic arsenicals. A portion of As(III) is methylated, predominantly in the liver, to methylarsonic acid and dimethylarsinic acid. The methylation process is the body’s principal mechanism of detoxification; the resulting metabolites are less toxic and more readily excreted.
Methylation efficiency in humans appears to decrease at high arsenic doses. When the methylating capacity of the liver is exceeded, exposure to excess levels of inorganic arsenic results in increased retention of arsenic in soft tissues. Cell culture studies suggest that the methylating process is inducible, since pretreatment with small amounts of arsenic over a prolonged period increases the methylating efficiency when a large dose is subsequently applied. Fish arsenic is apparently not biotransformed in vivo, but is rapidly excreted unchanged in the urine.
Arsenic is excreted primarily through the kidneys. After low-level exposure to inorganic arsenic, most of the urinary arsenic is present as methylated metabolites. Other less important routes of elimination of inorganic arsenic include feces, sweat, skin desquamation, and incorporation into hair and nails.
After a single intravenous injection of radiolabeled trivalent inorganic As(III) in human volunteers, most of the arsenic was cleared through urinary excretion within 2 days, although a small amount of arsenic was found in the urine up to 2 weeks later. The biologic half-life of ingested fish arsenic in humans is estimated to be <20 hours, with total clearance in approximately
Most tissues, except for skin, hair, and nails, rapidly clear arsenic.
Arsenic undergoes methylation to less-toxic metabolites in the liver.
Arsenic is excreted in the urine; most of a single, low-level dose is excreted within a few days after ingestion.
48 hours. Because arsenic is rapidly cleared from the blood, blood levels may be normal even when urine levels remain markedly elevated.
Challenge
(3) Analysis of a spot sample of the patient’s urine revealed 6,000 μg per liter (μg/L) (normal is <50 μg/L) as total arsenic. What factors could be responsible for this level, and what additional history would you elicit?
Physiologic Effects
Two mechanisms of arsenic toxicity that impair tissue respiration have been described. Arsenic binds with sulfhydryl groups and disrupts sulfhydryl- containing enzymes; As(III) is particularly potent in this regard. As a result of critical enzyme effects, there is inhibition of the pyruvate and succinate oxidation pathways and the tricarboxylic acid cycle, impaired gluconeogenesis, and reduced oxidative phosphorylation. Another mechanism involves substitution of As(V) for phosphorus in many biochemical reactions. Replacing the stable phosphorus anion in phosphate with the less stable As(V) anion leads to rapid hydrolysis of high-energy bonds in compounds such as ATP. That leads to loss of high-energy phosphate bonds and effectively “uncouples” oxydative phosphorylation.
Arsine gas poisoning results in a considerably different syndrome from that caused by other forms of arsenic. After inhalation, arsine rapidly fixes to red cells, producing irreversible cell-membrane damage. At low levels, arsine is a potent hemolysin, causing dose-dependent intravascular hemolysis. At high levels, arsine produces direct multisystem cytotoxicity.
Gastrointestinal, Hepatic, and Renal Effects
The gastrointestinal (GI) effects of arsenic generally result from exposure via ingestion; however, GI effects may also occur after heavy exposure by other routes. The fundamental GI lesion appears to be increased permeability of the small blood vessels, leading to fluid loss and hypotension. Extensive inflammation and necrosis of the mucosa and submucosa of the stomach and intestine may occur and progress to perforation of the gut wall. A hemorrhagic gastroenteritis may develop, with bloody diarrhea as a presenting symptom.
Arsenic intoxication may also result in hepatic toxicity, including toxic hepatitis and elevated liver enzyme levels. Autopsies of Japanese children poisoned with arsenic-contaminated milk revealed hepatic hemorrhagic necrosis and fatty degeneration of the liver. Chronic arsenic ingestion may lead to cirrhotic portal hypertension. Case reports have also linked chronic
Because it targets ubiquitous enzyme reactions, arsenic affects nearly all organ systems. Arsenic is strongly associated with lung and skin cancers and may cause other cancers.
Unlike other arsenicals, arsine gas causes a hemolytic syndrome.
Gastrointestinal effects are seen primarily after arsenic ingestion, and less often after inhalation or dermal absorption.
Acute arsenic toxicity may be associated with hepatic necrosis and elevated levels of liver enzymes.
painful dysesthesia, occur earlier and may predominate in moderate poisoning, whereas ascending weakness and paralysis may predominate in more severe poisoning. Those cases may at first seem indistinguishable from Guillain-Barré syndrome (i.e., acute inflammatory demyelinating polyneuropathy). Cranial nerves are rarely affected, even in severe poisoning. Encephalopathy has been reported after both acute and chronic exposures.
Onset may begin within 24 to 72 hours following acute poisoning, but it more often develops slowly as a result of chronic exposure. The neuropathy is primarily due to destruction of axonal cylinders (axonopathy). Nerve conduction and electromyography studies can document severity and progression. Subclinical neuropathy, defined by the presence of abnormal nerve conduction with no clinical complaints or symptoms, has been described in chronically exposed individuals.
Recovery from neuropathy induced by chronic exposure to arsenic compounds is generally slow, sometimes taking years, and complete recovery may not occur. Follow-up studies of Japanese children who chronically consumed arsenic-contaminated milk revealed an increased incidence of severe hearing loss, mental retardation, epilepsy, and other brain damage. Hearing loss as a sequela of acute or chronic arsenic intoxication has not been confirmed by other case reports or epidemiologic studies.
Dermal Effects
The types of skin lesions occurring most frequently in arsenic-exposed humans are hyperpigmentation, hyperkeratosis, and skin cancer. Patchy hyperpigmentation, a pathologic hallmark of chronic exposure, may be found anywhere on the body, but occurs particularly on the eyelids, temples, axillae, neck, nipples, and groin. The classic appearance of the dark brown patches with scattered pale spots is sometimes described as “raindrops on a dusty road.” In severe cases, the pigmentation extends broadly over the chest, back, and abdomen. Pigment changes have been observed in populations chronically consuming drinking water containing 400 ppb arsenic.
Arsenical hyperkeratosis occurs most frequently on the palms and soles. Keratoses usually appear as small corn-like elevations, 0.4 to 1 cm in diameter. In most cases, arsenical keratoses show little cellular atypia and may remain morphologically benign for decades. In other cases, cells develop marked atypia (precancerous) and appear indistinguishable from Bowen disease, which is an in situ squamous cell carcinoma discussed in Carcinogenic Effects.
Pigment changes and palmoplantar hyperkeratosis are characteristic of chronic arsenic exposure. Benign arsenical keratoses may progress to malignancy.
Respiratory Effects Smelter workers experiencing prolonged exposures to high concentrations of airborne arsenic at levels rarely found today had inflammatory and erosive lesions of the respiratory mucosa, including nasal septum perforation. Lung cancer has been associated with chronic arsenic exposure in smelter workers and pesticide workers.
Hematopoietic Effects Both acute and chronic arsenic poisoning may affect the hematopoietic system. A reversible bone marrow depression with pancytopenia may occur. Anemia and leukopenia are common in chronic arsenic toxicity, and are often accompanied by thrombocytopenia and mild eosinophilia. The anemia may be normocytic or macrocytic, and basophilic stippling may be noted on peripheral blood smears.
Reproductive Effects Arsenic is a reproductive toxicant and a teratogen. It is readily transferred across the placenta, and concentrations in human cord blood are similar to those in maternal blood. A published case report described acute arsenic ingestion during the third trimester of pregnancy leading to delivery of a live infant that died within 12 hours. Autopsy revealed intra-alveolar hemorrhage and high levels of arsenic in the brain, liver, and kidneys.
A study of women working at or living near a copper smelter where ambient arsenic levels were elevated reported increased frequencies of spontaneous abortions and congenital malformations. The frequency of all malformations was twice the expected rate and the frequency of multiple malformations was increased fivefold. However, a number of other chemicals, including lead, cadmium, and sulfur dioxide were also present, and thus it is difficult to assess the role of arsenic in the etiology of these effects.
Carcinogenic Effects In humans, chronic arsenic ingestion is strongly associated with an increased risk of skin cancer, and may cause cancers of the lung, liver, bladder, kidney, and colon; chronic inhalation of arsenicals has been closely linked with lung cancer. The precise mechanism of arsenic-related carcinogenicity is unknown. Arsenic does not induce genetic mutations in most test systems, but chromosomal damage has been reported in cultured mammalian cells, possibly as a result of arsenic’s effects on the enzymes involved in DNA replication and repair. Paradoxically, cancer associated with arsenic exposure has not been produced in experimental animals.
The carcinogenicity of arsenic in humans has been established, but no animal model has been developed.
Inhalation of high concentrations of arsenic compounds produces irritation of the respiratory mucosa.
Bone marrow depression may result from acute or chronic arsenic intoxication and may initially manifest as pancytopenia.
Increased frequency of spontaneous abortions and congenital malformations has been linked to arsenic exposure.
Clinical Evaluation
History and Physical Examination The source of exposure is identified in fewer than 50% of arsenic poisonings; however, a careful history and physical examination may improve these statistics. Because arsenic intoxication may affect multiple organ systems, a complete physical examination is imperative. In chronic ingestion, particular clues to arsenic poisoning may be provided by dermatologic and neurologic findings. The medical history should include: occupational history, diet, residential history (proximity to smelters, other industry, and hazardous waste sites), smoking history, condition of household, pets, hobbies (including use of pesticides or herbicides in farming or gardening), medications (including folk or naturopathic medications), source of drinking water, and home heating methods (wood- burning stoves and fireplaces).
Signs and Symptoms Acute Exposure Acute arsenic poisoning rarely occurs in the workplace today; it usually results from unintentional ingestion, suicide, or homicide. The fatal dose of ingested arsenic in humans is difficult to determine from case reports and depends upon many factors (e.g., solubility, valence state, etc.). The minimal lethal dose is in the range of 50 to 300 mg. The signs and symptoms of acute arsenic poisoning include the following:
Gastrointestinal: severe abdominal pain, nausea and vomiting, and bloody or rice-water diarrhea Cardiovascular and respiratory: hypotension, shock; ventricular arrhythmia; congestive heart failure; and pulmonary edema Neurologic: light-headedness; headache; weakness, lethargy; delirium; encephalopathy; convulsions; coma; and sensorimotor peripheral neuropathy Hepatic and renal: elevated liver enzymes; hematuria, oliguria, proteinuria; and acute tubular necrosis, renal cortical necrosis Hematologic: anemia, leukopenia, thrombocytopenia, and disseminated intravascular coagulation Other: rhabdomyalysis, garlic odor on the breath, and delayed appearance of Mees lines. As a result of inorganic arsenic’s direct toxicity to the epithelial cells of the gastrointestinal tract and its systemic enzyme inhibition, profound gastroenteritis, sometimes with hemorrhage, can occur within minutes to hours after acute ingestion. Symptoms may last for several days. Difficulty in
In acute arsenic poisoning, death is usually due to cardiovascular collapse and hypovolemic shock.
In many cases, the source of arsenic exposure cannot be identified.
swallowing, abdominal pain, vomiting, diarrhea, and dehydration may result. In subacute poisoning, however, the onset of milder GI symptoms may be so insidious that the possibility of arsenic intoxication is overlooked.
Arsenic has deleterious effects on the heart and peripheral vascular system. Capillary dilation with fluid leakage and third spacing may cause severe hypovolemia and hypotension. Cardiac manifestations have included cardiomyopathy, ventricular dysrhythmias (atypical ventricular tachycardia and ventricular fibrillation), and congestive heart failure.
A delayed sensorimotor peripheral neuropathy may occur after acute arsenic poisoning. Symptoms are initially sensory and may begin 2 to 4 weeks after resolution of the first signs of intoxication resulting from ingestion (shock or gastroenteritis). Commonly reported initial symptoms include numbness, tingling and “pins and needles” sensations in the hands and feet in a symmetrical “stocking-glove” distribution, and muscular tenderness in the extremities. Clinical involvement spans the spectrum from mild paresthesia with preserved ambulation to distal weakness, quadriplegia, and, in rare instances, respiratory muscle insufficiency.
Other findings in acute arsenic poisoning may include fever and facial edema. Several months after poisoning, transverse white striae (pale bands) on the nails called Mees lines (or Aldrich-Mees lines) may be seen, reflecting transient disruption of nail plate growth during acute poisoning. In episodes of multiple acute exposures, several Mees lines may occur within a single nail. In some cases, the distance of the lines from the nail bed may be used to roughly gauge the date of the poisoning episode. However, Mees lines are not commonly seen; of 74 patients with acute and chronic arsenic poisoning, Mees lines occurred in only 5% of the patients.
Respiratory tract irritation (cough, laryngitis, mild bronchitis, and dyspnea) may result from acute exposure to airborne arsenic dust. Nasal septum perforation, as well as conjunctivitis and dermatitis, has also been reported.
The toxicity of arsine gas is quite different from the toxicity of other arsenicals, requiring different emphases in the medical history, physical examination, and patient management. Arsine is a powerful hemolytic poison in both acute and chronic exposures. The clinical signs of hemolysis may not appear for up to 24 hours after acute exposure, thereby obscuring the relationship between exposure and effect. Initial symptoms of arsine poisoning may include headache, nausea, abdominal pain, and hematuria.
Chronic Exposure Skin lesions and peripheral neuropathy are the hallmarks of arsenic ingestion, and their presence should result in an aggressive search for this etiology. Neuropathy can occur insidiously in chronic toxicity without other
Onset of peripheral neuropathy may be delayed several weeks after the initial toxic insult.
Neuropathy may be the first sign of chronic arsenic toxicity.
Mees lines may be visible in the fingernails several months after acute arsenic exposure.
Specific tests: urine arsenic concentration.
Some arsenic compounds, particularly those of low solubility, are radiopaque, and if ingested may be visible on an abdominal radiograph.
Direct Biologic Indicators
The key diagnostic laboratory test for recent exposure is urinary arsenic measurement. The best specimen is a 24-hour urine collection, although spot urine specimens can be helpful in an emergency. Normal total urinary arsenic values are <50 μg arsenic per liter (As/L) in the absence of consumption of seafood in the past 48 hours; values in excess of 200 μg As/L are considered abnormal (ATSDR 2000a). Test results may be reported in micrograms arsenic per gram creatinine to avoid effects due to variation in urine output. Fish arsenic can significantly increase total urinary arsenic levels; therefore, it may be prudent to take a dietary history of the previous 48 hours or repeat the urinary arsenic test in 2 or 3 days. Human volunteers with an average pretest urinary arsenic level of 30 μg/L were given lobster tail for lunch. Four hours after eating, they had an average urinary level of 1,300 μg As/L. These values decreased to pretest levels within 48 hours after ingestion. Request for speciation of arsenic (i.e., analysis of organoarsenicals or different inorganic species, rather than total arsenic) may be considered. Speciated tests are more widely available than in the past; you may want to consult your local Poison Control Center for more information.
Arsenic blood levels, normally <7 μg per deciliter (μg/dL), are less useful than urinary arsenic measurements in following the clinical course of an acute poisoning case, because of the rapid clearance of arsenic from the blood.
Long after urine levels have returned to baseline, the arsenic content of hair and nails may be the only clue of arsenic exposure. However, because the arsenic content of hair and nails may be increased by external contamination, caution must be exercised in using the arsenic content of these specimens to diagnose arsenic intoxication.
Indirect Biologic Indicators
The standard tests listed above will aid in evaluating the status of an arsenic- exposed patient. The CBC can provide evidence of arsenic-induced anemia, leukopenia, thrombocytopenia, or eosinophilia. Although basophilic stippling on the peripheral smear does not confirm arsenic poisoning, it is consistent with the diagnosis. Liver transaminases are frequently elevated in acute and chronic arsenic exposure and can help confirm clinical suspicion. If arsenic neuropathy is suspected, nerve conduction velocity tests should be performed. Such tests may initially show a decrease in amplitude, as well as slowed conduction. Skin lesions in patients with chronic arsenic exposure may require biopsy to rule out skin cancer.
If arsenic toxicity is suspected, several tests can be performed to help confirm clinical suspicion.
When total urinary arsenic is measured, it is important to inquire about recent diet.
Challenge
(6) What further medical workup is indicated for the patient described in the case study? (7) What does the presence of palmar-plantar keratosis suggest about the time course of the patient’s arsenic exposure? (8) Who else in the case study is at risk for exposure to arsenic? (9) A urine specimen from the wife of the patient was found to contain total arsenic at a concentration of 300 μg/L, and a sample of the wife’s hair contained 150 parts per million (ppm) arsenic. Compare this to the patient’s 6,000 μg/L urinary arsenic level and 100 ppm arsenic in the hair. The wife has no signs or symptoms of chronic arsenic intoxication. How might these findings be explained?
Treatment and Management
Acute Exposure Be certain that appropriate decontamination of the patient has been carried out. Remove and double-bag contaminated clothing and all personal belongings (ATSDR 2000b).
Prehospital Management Quickly assess for a patent airway, and ensure adequate respiration and pulse. Maintain adequate circulation (ATSDR 2000b). Consult with the regional poison control center for advice regarding arsenic poisoning and appropriate treatment.
Skin Exposure Wash exposed skin and hair with mild soap and water, and rinse thoroughly with water (ATSDR 2000b). Use caution to avoid hypothermia, particularly with children and the elderly (ATSDR 2000b).
Eye Exposure Flush exposed or irritated eyes with plain water or saline for at least 15 minutes (ATSDR 2000b). Remove contact lenses if easily removable without additional trauma to the eye (ATSDR 2000b).
Ingestion Do not induce emesis (ATSDR 2000b). The effectiveness of activated charcoal is questionable, but administration of activated charcoal as an aqueous slurry in persons who are awake and able to protect their airway is recommended pending further evaluation in cases of ingestion of unknown quantities (ATSDR 2000b). Activated charcoal is most effective when administered within 1 hour of ingestion (ATSDR 2000b; Anonymous
Hemodynamic stabilization and gut decontamination are key factors in the initial management of acute arsenic intoxication.
