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MD Consult: Books: Goldman: Cecil Medicine: Chapter 20 – CHRONIC POISONING: TRACE METALS AND OTHERS

Goldman: Cecil Medicine, 23rd ed. Copyright © 2007 Saunders, An Imprint of Elsevier

Chapter 20 – CHRONIC POISONING: TRACE METALS AND OTHERS

 

Michael A. McGuigan

 

Definition

 

The term chronic poisoning refers to toxicity that develops during repeated or continuous exposure to a substance during many months or years. A trace metal, which by definition is present in minute quantities, usually refers to metals that are essential to an organism’s function, but this chapter includes a number of metals that are not physiologically required and does not discuss acute poisoning ( Chapter 111 ).

Epidemiology

 

The source of most metals and the two other substances discussed in this chapter is the environment—the home, the workplace, or the outdoors—and most of the exposures are unintentional. Because many of these metals are essential to normal physiologic functions, another source may be dietary supplements ( Chapter 237 ). The most common site of absorption is the gastrointestinal tract.

The medical literature on chronic low-level exposures is uneven. Although the clinical toxicology of each metal is presented individually, most if not all exposures involve a number of different metals, and the clinical impact of metal-metal interactions is poorly understood.

   Lead

 

Epidemiology

 

Lead poisoning was recognized more than 2000 years ago. Although lead poisoning is often considered a problem primarily in the children of lower socioeconomic status families living in dilapidated housing with peeling lead-based paint, lead poisoning also occurs in adults exposed in occupational or nonoccupational activities ( Table 20-1 ).
TABLE 20-1   — COMMON SOURCES OF ADULT LEAD EXPOSURES

Occupational Nonoccupational
Manufacturing Shooting firearms
Manufacture of storage batteries Remodeling or renovation activities
Secondary smelting Hobbies (e.g., casting, ceramics, stained glass)
Manufacture of primary batteries Retained bullets or gunshot wounds
Primary smelting Pica
Welding and cutting operations Contaminated food, liquid, or nontraditional medications
Construction
Special trade contractors
Painting, paperhanging, decorating
Lead abatement workers
Mining
Mining of lead and zinc ores
Wholesale trades
Wholesale distribution of electrical apparatus and equipment, wiring supplies, and construction materials
Retail trades
Automobile repair shops
Transportation, communication, electric, gas, and sanitary services

Pathobiology

 

Inhaled fine particulates (<5 μm in diameter) of inorganic lead reach the alveoli and are readily absorbed; larger particles come in contact with airway mucus and eventually are swallowed. Only 20 to 30% of orally ingested lead is absorbed. Organic lead compounds can also be absorbed through the skin. Absorbed lead distributes first into blood and soft tissue and then into bone, where more than 90% of total body lead is found. Factors contributing to bone demineralization (e.g., prolonged bedrest, pregnancy, menopause) promote the release of lead from bone. Lead is excreted primarily through the kidneys at a rate of about 30 μg/day, which may increase to 200 μg/day with higher body burdens.

Clinical Manifestations

 

Lead binds to sulfhydryl groups and adversely affects zinc- and calcium-dependent enzyme systems. This binding interferes with heme synthesis, DNA transcription, and calcium-dependent release of neurotransmitters and of protein kinase C, which regulate cell growth, learning, and memory. In addition, lead affects membrane integrity, steroid metabolism, and vitamin D synthesis in renal tubular cells, and it produces motor axon degeneration and segmental demyelination. The clinical manifestations of lead toxicity are roughly related to the blood lead level ( Table 20-2 ).
TABLE 20-2   — SUMMARY OF CLINICAL LEAD TOXICITY

Blood Lead Level (μg/dL) Effects
<10 Aminolevulinic acid dehydrase inhibition
15–30 Elevation of erythrocyte protoporphyrin
30–39 Mild elevations in blood pressure
Altered testicular function
40–49 Increased coproporphyrins and urinary aminolevulinic acid
Slowed peripheral nerve conduction
50–59 Reduced hemoglobin synthesis
Neurologic symptoms
60–69 Reproductive effects in women
80–90 Anemia
Encephalopathy symptoms
Nephropathy
100+ Encephalopathy signs

Cardiovascular System

 

A cross-sectional study of 2165 women aged 40 to 59 years found that a change in blood lead levels from the lowest quartile (mean, 1.0 μg/dL; range, 0.5 to 1.6 μg/dL) to the highest quartile (mean, 6.3 μg/dL; range, 4.0 to 31.1 μg/dL) was associated with a significant increase in systolic (by 1.7 mm Hg) and diastolic (by 1.4 mm Hg) blood pressures. At blood lead levels between 10 and 40 μg/dL, lead increases systolic blood pressure by 1 to 2 mm Hg and diastolic pressure by 1.4 mm Hg for every doubling of the blood lead level. Workers with mean blood lead levels between 40 and 70 μg/dL have an increased risk of death from renal andhypertensive cardiovascular disease. The progression, mechanisms, and effects of therapeutic interventions are unclear in lead-associated hypertension.

Reproductive System

 

Workplace exposure to lead is associated with decreased fertility, spontaneous abortions, stillbirths, low birthweights, and increased infant mortality. At mean blood lead levels above 23 μg/dL, lead has a direct toxic effect on spermatogenesis, resulting in decreased sperm counts and abnormal sperm morphology and function.

Renal System

 

Lead accumulates in proximal tubule cells. Reported clinical findings include Fanconi’s syndrome, increased urate excretion, chronic interstitial nephritis, and interference in the renin-aldosterone system. In a population with a mean blood lead level of 8.1 μg/dL, an increase in blood lead level of 10 μg/dL was associated with a decrease in creatinine clearance of 10.4 mL/min.

Nervous System

 

Chronic encephalopathy ( Chapter 439 ) is more common than acute encephalopathy. Early encephalopathic manifestations include changes in cognitive function and mood: early morning sleep disturbances, headache, irritability, lassitude, and loss of libido. Abnormalities in cognition or visual-motor function may be evident on psychometric testing. These findings may be found in workers with blood levels as low as 30 μg/dL but are more common with blood lead levels in the range of 40 to 60 μg/dL. The decrease in neuropsychological performance may be comparable to what would be expected during aging of up to 20 years, although debate continues about the predictability of the effects of blood lead levels below 70 μg/dL. Many of these manifestations respond at least partially to a reduction in the blood lead level.

Lead-induced peripheral axonal neuropathy ( Chapter 446 ) most commonly involves the motor nerves, tending to be more severe in the upper extremities and on the dominant side. A subclinical decrease in ulnar nerve motor conduction velocity has been demonstrated at blood lead levels as low as 30 μg/dL. Lead poisoning also predisposes to the development of carpal tunnel and tarsal tunnel syndromes ( Chapter 446 ).

Hematologic System

 

Lead affects the red cell membrane and interferes with enzymes involved in the synthesis of hemoglobin. The traditional findings in severe poisoning include a hypochromic microcytic anemia and basophilic stippling ( Chapter 163 ).

Diagnosis

 

The initial steps in diagnosis of lead poisoning are to identify people involved in high-risk activities (see Table 20-1 ) and to determine the levels of lead in the venous (not capillary) blood. The diagnosis of lead poisoning should not rely on clinical symptoms and signs because these develop late and generally correlate poorly with blood lead levels. The blood lead level that triggers an intervention is not well established for adults, and no national guidelines exist for managing adults with lead poisoning. It is in the best interest of the patient to follow the most conservative standards: a confirmed venous blood lead level of 40 μg/dL or more should trigger an intervention, including improved industrial hygiene, better dust control, and increased ventilation.

Treatment

 

 

 

 

 

Treatment is designed to prevent further exposure, to reduce the blood lead level to an acceptable range, and to repair any existing damage. Removal of an individual from a lead environment is recommended if a blood lead level is 50 μg/dL or higher on two tests separated by 2 weeks or if a medical condition consistent with lead poisoning has been identified. Removal from the lead source often is associated with a gradual reduction in blood lead levels. Chelation therapy is generally recommended if symptoms or signs are present or if the blood lead level is above 60 μg/dL ( Table 20-3 ).

Calcium disodium ethylenediaminetetraacetic acid (CaNa2EDTA) is the first-line drug for treating asymptomatic adults with high blood lead levels. In the treatment of symptomatic lead poisoning (with or without encephalopathy), CaNa2EDTA is used in conjunction with dimercaprol (2,3-dimercaptopropanol or BAL). Larger doses of CaNa2EDTA (50 to 75 mg/kg/day) are used for more severely poisoned patients. A third chelator, succimer (meso-2,3-dimercaptosuccinic acid, DMSA), is approved for the treatment of children with blood lead levels above 45 μg/dL; although succimer has not been approved by the Food and Drug Administration (FDA) for the treatment of adult lead poisoning, adults have been successfully treated with succimer and it should be considered in place of CaNa2EDTA monotherapy. D-Penicillamine (3-mercapto-D-valine or penicillamine) is not recommended for the treatment of adult lead poisoning because of the high incidence of adverse drug reactions.

Chelation removes lead from the blood and soft tissues, but little is removed from bone. Redistribution of lead from deep stores after chelation may result in a rebound of blood lead levels and the redevelopment of clinical toxicity. For this reason, individuals who have been chelated should have blood lead levels measured 2 weeks after the course of chelation has been completed. In general, the clinical response to chelation therapy is variable and the data demonstrating improved outcomes are not robust. After chelation, blood lead levels tend to rise because of redistribution of lead. If the blood lead level rises into the toxic range or if symptoms recur, another course of chelation is indicated with the same dose and duration as in the original course.
TABLE 20-3   — GENERAL GUIDELINES FOR CHELATION THERAPY

Drug Adult Dose Indications Cautions and Contraindications
Dimercaprol, British antilewisite (BAL) 3 to 5 mg/kg (75 mg/m2) IM every 4 hours for 2 days; then 3 mg/kgIM every 12 hours for 1 day; then 3 mg/kg one or two times daily Lead: Symptomatic poisoning Administration is by deep IM injection; injections are painful.
The vehicle is peanut oil—do not use intravenously. Use is contraindicated if peanut allergy exists.
CaNa2EDTA 20 to 30 mg/kg/day (1000 to 1500 mg/m2/day) as a continuous IV infusion for 5 days Lead: Symptomatic poisoning or asymptomatic patients with high blood lead levels Do not use Na2EDTA.
Manganese: Symptomatic patients with blood, serum, or urine manganese levels above reference values It can be given IM in two or three divided doses.
High doses of CaNa2EDTA increase zinc excretion and may be toxic to the renal glomerulus and proximal tubule.
Dimercaptopropanesulfonate (DMPS) 100 mg orally four times per day for 7 days Arsenic: Symptomatic patients with urine arsenic levels ≥50 μg/L
May repeat therapeutic course after 7 days of no therapy if levels still elevated Asymptomatic patients with urine arsenic levels >200 μg/L
Manganese: Symptomatic patients with blood, serum, or urine manganese levels above reference values
Bismuth: Symptomatic patients with bismuth blood levels >50 μg/L or urine levels >150 μg/L
Deferoxamine 6 g as a continuous IV infusion given in 24 hours Aluminum: Symptomatic patients with serum aluminum levels >100 μg/L
May repeat if serum levels are still elevated
Succimer 10 mg/kg (350 mg/m2) orally every 8 hours for 5 days; then 10 mg/kg every 12 hours for 14 days Lead: Symptomatic poisoning or asymptomatic patients with high blood lead levels Succimer has a sulfur-like odor
Mercury: Symptomatic patients with mercury blood levels >10 μg/L or urine levels >20 μg/L

   Mercury

 

Definition

 

There are three chemical forms of mercury. Elemental or metallic mercury (Hg0, quicksilver) is a silver liquid at room temperature. Inorganic mercury is in either a mercurous (Hg+) or a mercuric (Hg++) state. Organic mercurials are attached to short (ethyl or methyl) or long (alkyl or aryl) carbon chains. Each form of mercury may be found in a variety of occupations and products.

Epidemiology

 

The different chemical forms represent different delivery systems by which mercury enters and is distributed throughout the body. From a clinical perspective, the most important target organ is the central nervous system even though the kidney accumulates the most mercury regardless of the chemical type. Chronic poisoning with any of the chemical forms of mercury results in central nervous system toxicity. Ingestion of organic mercury is the most efficient way to get mercury into the brain, inhalation of elemental mercury vapor is second, and ingestion of inorganic mercury is the least efficient.

Pathobiology

 

Mercury produces toxicity by binding to sulfhydryl groups, thereby inhibiting enzyme systems and disrupting cell membrane integrity. Mercury also binds to amide, amine, carboxyl, and phosphoryl groups. Methyl mercury inhibits choline acetyltransferase, a critical enzyme in the formation of acetylcholine.

Elemental mercury is or has been used in dental amalgams, calibration instruments, electroplating, gold extraction, manometers, and thermometers. Elemental mercury pooled under carpets or floorboards in homes has resulted in clinical toxicity. Ingested elemental mercury is poorly absorbed from the gastrointestinal tract and causes virtually no toxicity. Conversely, nearly 75% of inhaled elemental mercury vapor is absorbed through the lungs. Once it is absorbed, elemental mercury is distributed to the tissues and red blood cells, where it is oxidized to the mercuric form. Some elemental mercury crosses the blood-brain barrier, and oxidation within the central nervous system leads to accumulation of divalent mercury in the brain because ionized mercury does not readily cross the blood-brain barrier.

Inorganic mercury may be a component of disinfectants, fireworks, preservatives, and photograph developing chemicals. Inorganic mercury solutions are corrosive to the gastrointestinal tract, but up to 15% of ingested inorganic mercury is absorbed through the gastrointestinal mucosa. After absorption, the inorganic mercury salt is ionized and penetrates the blood-brain barrier poorly. However, absorbed divalent mercury can be reduced to the metallic form that will cross the blood-brain barrier.

Organic mercurials are used as pesticides, preservatives, and disinfectants. Coal-fired power plants are a major source of mercury in the environment. Elemental and inorganic mercurials deposited in the environment are bioconverted into organic mercury compounds that are a recognized contaminant of the food chain, particularly in fish. Consumption of fish is the source of nearly all of the methyl mercury in the general population. The FDA and the Environmental Protection Agency recommend avoidance of fish with the highest mercury concentrations—king mackerel, shark, swordfish, and tilefish from the Gulf of Mexico. Women of childbearing age and pregnant women should limit their consumption of medium-mercury fish: fresh tuna steaks, canned white or albacore tuna, grouper, orange roughy, saltwater trout, bluefish, lobster, halibut, haddock, snapper, and crabs. In addition, caution is urged regarding the consumption of fish from local lakes and ponds that may be more polluted than commercial fish sources.

Organic mercury is highly lipid soluble, well absorbed through the gastrointestinal tract, and widely distributed throughout the body. Organic mercury compounds are metabolized in the body; longer chain mercury compounds are rapidly metabolized to inorganic mercury, whereas short-chain mercury compounds (e.g., methyl mercury) are slowly metabolized to inorganic mercury. Organic mercury readily crosses the blood-brain barrier, and oxidation within the central nervous system leads to accumulation of mercuric ion in the brain.

Clinical Manifestations

 

The chronic inhalation of elemental mercury vapor results in two syndromes. The first syndrome consists of neuropsychiatric manifestations, gingivostomatitis, and tremor. The tremor ( Chapter 434 ) is evident at rest or with motion and may be aggravated with purposeful movement. The second syndrome is erythism, a neuropsychiatric constellation of findings that includes fatigue, insomnia, memory impairment, nervousness, irritability, shyness, social withdrawal, loss of confidence, timidity, and depression.

Chronic occupational exposure to inorganic mercury may cause subclinical psychomotor and neuromuscular abnormalities as well as long-term behavioral impairment. Neuropsychiatric abnormalities (in attention, memory, construction, and motor performance) appear to be dose related ( Chapter 425 ).

Methyl mercury poisoning is cumulative and develops during several years. Based on epidemics of methyl mercury poisoning in Japan and Iraq in which large quantities of organic mercury were consumed, the initial symptoms are fatigue and perioral and extremity paresthesia, followed by difficulty with hand movements and disturbances of vision. The classic picture of methyl mercury poisoning is the gradual onset of ataxia, constricted visual fields, and dysarthria. Other findings are paresthesia, deafness, incoordination, loss of voluntary movement, and mental retardation. The full picture of toxicity is that of psychological, cerebellar, sensory, and motor abnormalities. However, moderate amounts of methyl mercury in the diet have not been implicated as causing adverse effects in adults; most concern relates to potential toxic effects on the fetus and its developing central nervous system.

Diagnosis

 

The diagnosis of mercury poisoning requires a history of exposure, compatible clinical findings, and elevated mercury levels in blood or urine.

Mercury Levels

 

The mean total mercury levels in whole blood and urine in the general population are 1 to 8 μg/L and 4 to 5 μg/L, respectively. Although elevated blood or urine mercury levels are consistent with clinical toxicity, the correlation of clinical signs or symptoms with blood or urine mercury levels is poor because of substantial intra-individual and inter-individual variations. For example, data in urban adults (mean age, 59 years) found no significant association between blood mercury levels (mean, 2.1 μg/L; range, 0 to 16 μg/L) and neurobehavioral performance.

A ratio of red blood cell to plasma mercury of 1:1 suggests inorganic mercury poisoning, whereas a ratio of 10:1 suggests organic mercury toxicity. Red blood cell and plasma mercury levels could be requested if the source and type of the mercury exposure are unknown. Methyl mercury blood levels of 3 to 5 μg/dL may be found in patients with symptoms. Determination of a methyl mercury level is recommended if the exposure is to a contaminated environmental source.

Treatment

 

 

 

 

 

Asymptomatic patients with elevated urine mercury levels should have the analyses repeated after a 4-week period without fish consumption.

A patient with mercury poisoning should be immediately removed from the contaminated environment; the source of the mercury must then be identified and removed. Treatment is primarily symptomatic and supportive.

Chelation therapy (see Table 20-3 ) is used to increase the excretion of mercury even though improved clinical outcomes have not been demonstrated; increased urine excretion of mercury alone has become an accepted if empirical clinical goal. There is little agreement on the indications for initiation or cessation of chelation therapy. The presence of clinical toxicity combined with elevated mercury levels is an accepted indication for chelation therapy. The role of chelation therapy for asymptomatic individuals with mercury levels above background values is controversial. A reasonable end point for chelation is the achievement of background levels of mercury in urine or blood (<20 μg/L or 10 μg/L, respectively). Fish eaters with elevated mercury levels should avoid eating any fish or shellfish for 1 month, after which analysis of mercury levels in blood or urine should be repeated. If mercury levels have come down to reference values, low-mercury fish (shrimp, canned light tuna, salmon, pollock, catfish) can be reintroduced into the diet at a frequency of no more than two meals per week.

Succimer (see Table 20-3 ) is the chelator of choice because it can be given orally and has been effective in reducing brain levels of methyl mercury in animal studies. D-Penicillamine is less effective than succimer and has a higher adverse drug reaction rate. Dimercaprol is not recommended because of its potential to shift mercury from peripheral tissues into the brain. N-Acetylcysteine has been proposed as a chelator of methyl mercury, and repeated oral administration may interrupt the enterohepatic recirculation of methyl mercury; however, use of this drug for this purpose has not undergone clinical trials and is not approved by the FDA.

   Arsenic

 

Definition

 

Arsenic is a naturally occurring omnipresent element that exists in three valence states: elemental or metallic arsenic (As0), trivalent (arsenite, As3+), and pentavalent (arsenate, As5+). The trivalent form of arsenic (arsenite) is the most toxic and is responsible for the worldwide public health concern about chronic arsenic poisoning. Organic alkane arsenicals are of low toxicity, and elemental arsenic is virtually nontoxic.

Epidemiology

 

The major sources of human exposure to arsenic are the environment (mining, seafood, groundwater) and industry (pesticides, pigments, wood preservatives, glass or metal manufacturing, electronics, folk remedies). The arsenic content in the average North American adult diet is less than 1 μg/kg/day. Arsenic in seafood is primarily in the form of organic arsenicals, and the content is variable; freshwater fish may have up to 2 mg/kg, whereas lobster may have up to 22 mg/kg. The Environmental Protection Agency drinking water standard is 10 μg/L.

Pathobiology

 

Nearly 90% of ingested or inhaled arsenic is absorbed; little arsenic is absorbed through intact skin. Absorbed arsenic is widely distributed throughout the body, but no form of arsenic readily crosses the blood-brain barrier. Pentavalent arsenic and trivalent arsenic undergo oxidation-reduction reactions, converting one form to the other. Pentavalent arsenic is reduced by glutathione to the more toxic trivalent form. Methylation of trivalent arsenic produces the less toxic monomethylarsenate and dimethylarsenate metabolites that are excreted in the urine. Organic arsenicals, such as those found in seafood, are not toxic, are not metabolized to toxic forms of arsenic, and are rapidly excreted in the urine with an elimination half-life of 4 to 6 hours.

Arsenite (As3+) binds to sulfhydryl groups, resulting in inhibition of many enzyme systems (glycolysis, pyruvate dehydrogenase, Krebs cycle) and decreased production of adenosine triphosphate. Arsenate (As5+) replaces phosphate in microsomal enzyme systems, resulting in uncoupling of oxidative phosphorylation and decreased production of adenosine triphosphate. The pentavalent arsenate does not bind to sulfhydryl groups. Inorganic arsenic is a human carcinogen.

Clinical Manifestations

 

Chronic poisoning develops after ingestion or inhalation of arsenic during weeks to months, depending on the daily dose. Clinical manifestations develop gradually and are highly variable among exposed individuals. Typical initial manifestations include nonspecific complaints such as a metallic taste in the mouth, anorexia, weight loss, malaise, and weakness.

Skin lesions are some of the most common and earliest nonmalignant identifiable toxic effects. Typical dermal findings include melanosis (trunk and extremities), hyperpigmentation (tongue, oral mucosa, axillae), hyperkeratosis (palms, soles), and brittle nails. Less common or late findings include alopecia and white transverse bands (Mees’ lines) ( Chapter 467 ).

Later findings involve the nervous system and carcinogenesis. Neurologic effects are both central and peripheral. Central effects include mild dementia ( Chapter 425 ) and headache; cranial nerves are normal. Peripheral sensory and motor neuropathies ( Chapter 435 ) develop in a stocking-and-glove distribution and cause muscle weakness, muscle atrophy, and ataxia.

Malignant neoplasms include Bowen’s disease, basal cell carcinoma, and squamous cell carcinomas ( Chapter 214 ). Lung cancer ( Chapter 201 ) may result from the inhalation of dust containing high levels of arsenic. Arsenic in drinking water has been associated with leukemias, bladder cancer, renal cancer, hepatic cancer, and uterine cancer ( Chapter 185 ). The cancer risk from arsenic in drinking water may be dose related. Studies of populations outside the United States exposed to arsenic in drinking water show increases in cancer only at drinking water arsenic concentrations of more than several hundred micrograms per liter. Studies of United States populations exposed to average drinking water arsenic concentrations of about 190 μg/L have not demonstrated evidence of increased cancer.

Cardiovascular disease includes atherosclerosis, coronary artery disease, and hypertension. Blackfoot disease, peculiar to the southwest coast of Taiwan, is a form of peripheral vascular disease that results in gangrene of the lower extremities. Other manifestations of exposure to arsenic in drinking water include chronic cough, type 2 diabetes, and reproductive abnormalities such as congenital malformations, miscarriage, and low birthweight.

Diagnosis

 

The diagnosis of chronic arsenic poisoning depends on an appropriate history of exposure (including a source), compatible clinical manifestations, and documentation of an elevated body burden of arsenic. Principal sources of arsenic are environmental (contaminated water, air, soil) and occupational or industrial. Although seafood may be a source of organic arsenic, it is not associated with clinical toxicity.

Arsenic can be measured in the hair, blood, or urine. Hair analysis is a suboptimal method of determining chronic toxicity. Environmental arsenic is adsorbed to the external surface of the hair and is difficult to remove by washing, arsenic levels vary within a single hair and among hairs, and there is a significant inter-individual variability in adsorption of arsenic to hair. Nonetheless, the normal arsenic hair levels are less than 1 μg/g dry weight, and arsenic levels in hair from people with chronic toxicity range from 1 to 5 μg/g or more.

Blood levels of arsenic reflect only very recent exposures and are not reliable indicators of chronic exposure to low levels of arsenic. For example, there is no correlation between arsenic blood levels and arsenic drinking water levels of 6 to 125 μg/L.

Normal urine arsenic levels are 50 μg/L or 25 μg/24 hours in the absence of seafood consumption. Urine arsenic levels above 200 μg/L are abnormal. The average urine arsenic levels among people with chronic toxicity are 207 μg of inorganic arsenic per gram of creatinine. Because urine analysis measures total arsenic, elevated levels should be speciated to determine the fractions of inorganic arsenic and organic arsenic. If this analysis is not possible, seafood should be eliminated from the patient’s diet for 1 week and the urine analysis then repeated.

A nerve conduction study is not a reliable tool for diagnosis of chronic arsenic toxicity. Among patients with elevated urine arsenic levels, the results of nerve conduction tests do not correlate well with the presence or absence of clinical neuropathy.

Treatment

 

 

 

 

 

Treatment approaches can be stratified according to symptoms and inorganic arsenic urine levels ( Table 20-4 ). All patients who are symptomatic or who have inorganic arsenic urine levels of 50 μg/L or above should be removed from the source of the arsenic.

Dimercaptopropanesulfonate (DMPS) is the most widely studied chelating agent for chronic arsenic poisoning and the drug of choice, although it is not approved by the U.S. FDA. DMPS forms a water-soluble complex with monomethylarsenic that is excreted in the urine. In a randomized trial, DMPS therapy (100 mg orally four times per day on alternate weeks for 7 weeks) increased urine arsenic excretion and improved weakness, pigmentation, and lung disease, but it did not improve hematologic and blood chemistry abnormalities, neuropathy, hepatomegaly, keratosis, or skin histology[1]. Chelation should continue until the urine arsenic level is below 50 μg/L. Succimer has not been successful for treating chronic arsenic toxicity, and dimercaprol is not recommended because the lipid-soluble dimercaprol-arsenic complex penetrates the blood-brain barrier.
TABLE 20-4   — ARSENIC TREATMENT STRATIFICATION

Inorganic Arsenic Urine Levels Symptomatic Asymptomatic
<50 μg/L Supportive care No treatment
50–200 μg/L Chelation[*] Monitor 24-hour urine levels monthly
>200 μg/L Chelation[*] Chelation[*]
* Using DMPS (see Table 20-3 ).

   Cadmium

 

Epidemiology

 

Cadmium may be found as the metal and in a number of industrial chemicals. Cadmium may enter the environment through contamination, fuel combustion, or fertilizers. The majority of cadmium is used occupationally in nickel-cadmium batteries and to protect polyvinyl chloride against heat and light. Cadmium is used as a pigment in coloring “red bags” used for infectious hospital waste. When they are incinerated, these bags release cadmium into the environment, so medical waste incinerators are an important environmental source of cadmium. The largest source of most human exposure to cadmium is dietary, with an average daily intake of 10 to 30 μg. Cadmium exposure is doubled in people who smoke tobacco.

Pathobiology

 

Approximately 25% of inhaled cadmium is absorbed. Although only 5% of ingested cadmium is normally absorbed, gastrointestinal absorption is increased in the presence of calcium or iron deficiency or high dietary fat. Cadmium concentrates in the liver and kidneys. Cadmium is poorly excreted from the body; the half-life for elimination from kidney parenchyma is estimated to be more than 6 years. The kidney is the primary target organ in chronic toxicity.

Clinical Manifestations

 

The clinical picture of chronic cadmium toxicity is one of irreversible renal toxicity ( Chapter 123 ). Proximal tubule damage results in high urine concentrations of low-molecular-weight proteins, amino acids, glucose, phosphate, and calcium. Decreased glomerular filtration rate and nephrolithiasis may occur. Renal failure is common.

The renal pathophysiologic process may result in calcium deficiency, osteoporosis, osteomalacia, and bone fractures. Other clinical manifestations of chronic cadmium poisoning include male infertility, slowing of visual-motor functioning, and peripheral neuropathies.

The Environmental Protection Agency and the International Agency for Research on Cancer have designated cadmium a probable human carcinogen. However, this designation is controversial, and chronic exposure to cadmium may not increase cancer rates. For example, residents of a cadmium-polluted village in England had no increase in cancer rates; a study of residents of a cadmium-polluted area in Belgium found no increase in prostate, kidney, or urinary tract cancers; a retrospective comparison of Japanese residents in high, low, and no cadmium-polluted areas found no differences in cancer mortality; and a study of copper-cadmium alloy workers found no increased risk of lung cancer.

Diagnosis

 

A tentative diagnosis of chronic cadmium poisoning can be confirmed by measuring elevated urinary cadmium levels (>5 μg/L) and elevated urinary microprotein levels, particularly α1-microglobulin.

Treatment

 

 

 

 

 

Treatment of the toxic effects of cadmium is symptomatic and supportive. There is no accepted way to reduce the body burden of cadmium. The use of CaNa2EDTA or dimercaprol may increase nephrotoxicity. Succimer and N-acetylcysteine have shown favorable results in animal studies, but neither has been adequately evaluated in human studies.

   Manganese

 

Definition

 

Manganese is an increasingly important toxin, both environmentally and occupationally. Manganese exists as a metal (metallic manganese, ferromanganese), as inorganic manganese (e.g., chloride or sulfate salts), or as organic manganese.

Epidemiology

 

Metallic manganese is used in steel production. Inorganic manganese (Mn2+, Mn3+, and Mn4+) is most commonly found in industry and in the environment. Various inorganic manganese compounds are involved in the manufacture of animal feed, batteries, fertilizers, fireworks, fungicides, matches, and potassium permanganate. Organic manganese compounds are used as a fuel oil additive, as fungicides, and as a gasoline additive (methylcyclopentadienyl manganese tricarbonyl, MMT).

Manganese is an essential nutrient, acting as a cofactor in enzymatic reactions involving bone mineralization as well as protein and carbohydrate metabolism. As such, it is often a component of parenteral nutrition preparations, and chronic infusion has resulted in manganese toxicity. Substantial exposure to manganese occurs in people who work in welding, mining, and foundry occupations. People who work with gasoline or as automobile mechanics may be exposed to MMT.

Pathobiology

 

Manganese is absorbed through the gastrointestinal and respiratory tracts and is distributed widely throughout the body. Manganese accumulates in the globus pallidus of the basal ganglia. Bile is the principal route of excretion. The elimination half-life is approximately 40 days but is longer for manganese in the central nervous system.

The primary target organ is the central nervous system, but the exact mechanisms of toxicity are unclear despite the fact that manganese adversely affects enzymes, receptors, and transport systems. A characteristic finding in chronic manganese poisoning is the selective destruction of dopaminergic neurons. The pathophysiologic mechanism is uncertain, but one hypothesis is that Mn2+ causes oxidation, production of free radicals or reactive oxygen species, or depletion of antioxidants.

Clinical Manifestations

 

People who work with manganese have developed a syndrome similar to but not identical with Parkinson’s disease ( Chapter 433 ). Findings include an extrapyramidal syndrome (masklike facies, tremor of the extremities at rest or on extension, bradykinesia, stooped posture, shuffling gait, propulsion abnormalities).

Parkinson’s disease and manganese-induced parkinsonism are similar, but several clinical characteristics may help distinguish between the two. Manganese-poisoned patients have a “cock walk” and have a propensity to fall backward when they are pushed. Manganese-poisoned patients often exhibit psychological disturbances early in the disease process. The so-called manganese madness includes aggression, irritability, nervousness, and destructive behavior. Uncontrollable spasmodic crying or laughter, singing or dancing, or unfocussed running around have been described.

Diagnosis

 

The initial diagnosis of chronic manganese poisoning relies on a history of exposure and consistent clinical findings. In patients with significant central nervous system findings, a T1-weighted magnetic resonance imaging examination showing bilateral, symmetrical hyperdensities in the globus pallidus lends strong support to the diagnosis of chronic manganese poisoning.

Manganese levels in body fluids are helpful in establishing a diagnosis. Reference ranges have been established: blood, 40 to 140 μg/L; serum, 1.5 to 26.5 μg/L; and urine, 9.7 to 10.7 μg/L.

Treatment

 

 

 

 

 

Treatment of chronic manganese toxicity starts with removing the source of the manganese and providing supportive care. The results of chelation with CaNa2EDTA or DMPS (see Table 20-3 ) have been equivocal. Although levodopa responsiveness is a hallmark of Parkinson’s disease, welders with manganese-induced parkinsonism treated with levodopa showed no improvement over placebo-treated control subjects[2].

   Nickel

 

Epidemiology

 

Nickel is absorbed through the lungs, gastrointestinal tract, and skin. Water-soluble nickel compounds (e.g., nickel chloride or sulfate) are absorbed better than insoluble nickel is. Approximately 25% of the nickel in drinking water is absorbed. Nickel applied to the skin is absorbed into the skin but may not reach the circulation. The urine is the primary means of excretion of nickel from the body.

Pathobiology

 

Nickel is used in a large number of metal alloys and in batteries, electroplating (e.g., table cutlery and some jewelry), coins, surgical staples, and some joint prostheses. Nickel also is present in drinking water; the Environmental Protection Agency standard is 0.02 mg/kg/day.

Nickel appears to be an essential element in the body, but the physiologic role of nickel in the body is unclear. Nickel crosses the cell membrane through calcium channels and competes with calcium for some receptors.

Clinical Manifestations

 

Contact dermatitis ( Chapter 464 ) is the most common manifestation of nickel toxicity. Exposure to consumer products containing nickel, particularly jewelry, causes sensitization and contact dermatitis in as many as 30% of people. Once sensitization has occurred, the severity of subsequent reactions is related to the dose of nickel.

Chronic occupational exposures to nickel dusts and fumes have been associated with respiratory tract disease, including nasal, laryngeal, and lung cancers ( Chapter 185 ). The Environmental Protection Agency identifies nickel dust and nickel subsulfide as class A human carcinogens. Exposures to nickel in nonindustrial settings, from ingestion of nickel in water or food or from dermal contact, have not been associated with an increased risk of cancer.

Diagnosis

 

Nickel levels in blood or urine are not useful in establishing either excessive exposure or risk of disease.

Treatment

 

 

 

 

 

There is no specific treatment of nickel-induced dermal sensitivity.

   Other Toxic Metals

 

   Aluminum

 

Epidemiology

 

Aluminum is the most abundant metal. It is widely available in consumer products such as food, water, cookware, food wraps, cans, antiperspirants, medications (especially antacids and phosphate binders), and dialysate fluids. North Americans consume 7 to 9 mg of aluminum in their diets each day. Industrial exposures to aluminum may result in significant toxicity.

Pathobiology

 

Gastrointestinal tract absorption of aluminum ranges from 0.1 to 1.0%. Once it is absorbed, aluminum is bound to transferrin and distributed throughout the body, concentrating in bone and lung. The kidneys are the primary route of aluminum excretion, and a compromised ability to excrete aluminum is an important factor in development of aluminum toxicity outside of the occupational setting. Rare individuals may accumulate significant amounts of aluminum from antiperspirants.

Aluminum blocks the incorporation of calcium into bones and inhibits osteoblastic and osteoclastic activity. In patients with renal failure, aluminum has been identified as a potential contributor to anemia, dialysis encephalopathy, and renal osteodystrophy.

Clinical Manifestations

 

The central nervous system is a target organ for aluminum toxicity. The findings in dialysis encephalopathy ( Chapters 157 , 236 , and 443 ), which develops during months, include stuttering or stammering speech, directional disorientation, personality changes, myoclonus, motor apraxia, convulsions, and hallucinations. Industrial aluminum workers have developed cognitive defects, depression, incoordination, poor memory, and tremor. The relationship between aluminum exposure and Alzheimer’s disease is controversial.

Chronic exposure to excessive aluminum may cause osteomalacia ( Chapter 265 ), spontaneous fractures, and bone pain. Hypochromic, microcytic anemia ( Chapter 163 ) unresponsive to iron therapy correlates with aluminum levels in the plasma or erythrocytes. Aluminum workers have increased risks for development of lung or bladder cancer ( Chapter 185 ).

Diagnosis

 

The background serum aluminum levels in normal individuals are less than 10 μg/L. Patients undergoing chronic dialysis may have serum aluminum levels up to 50 μg/L. Levels above 60 μg/L indicate increased absorption; serum levels above 100 μg/L are potentially toxic; and serum levels above 200 μg/L are usually associated with clinical symptoms and signs of toxicity.

Treatment

 

 

 

 

 

Elevated serum aluminum levels can be brought down with extracorporeal clearance techniques, such as hemodialysis and hemofiltration. Deferoxamine chelates aluminum, and its use (see Table 20-3 ) is indicated when serum aluminum levels exceed 100 μg/L.

   Beryllium

 

Epidemiology

 

Beryllium occurs naturally in rocks, coal, oil, soil, and volcanic dust. Commercially, beryllium is used in metal alloys for aerospace, aircraft, sports equipment (golf clubs, bicycle frames), and automotive manufacturing; in electronics and computers; in ceramics; and in defense weapons. Beryllium is naturally present in tobacco and may be inhaled during smoking.

Pathobiology

 

Inhaled beryllium is cleared from the respiratory tract by the mucociliary action and alveolar macrophages. Once it is absorbed, beryllium is distributed to the bone, liver, kidneys, lung parenchyma, and lymphatic system. The kidney is the primary route of beryllium excretion.

Repeated exposure to beryllium causes a cell-mediated immune response involving T lymphocytes and release of TH1 cytokines in genetically susceptible persons ( Chapter 93 ). The cell-mediated response is persistent and results in the accumulation of immune effector cells (sensitized T lymphocytes, macrophages) that form granulomas and mononuclear cell infiltrations. Dermal exposure to beryllium may cause irritative or atopic dermatitis as well as beryllium-containing foreign bodies and granulomas. The Environmental Protection Agency considers beryllium to be a probable human carcinogen.

Clinical Manifestations

 

Chronic beryllium disease is a progressive systemic hypersensitivity disease affecting the lungs and lymphatic system ( Chapter 93 ). Clinical effects include progressive dyspnea, chest pain, weight loss, fatigue, anorexia, and fevers. Skin lesions, lymphadenopathy, and hepatosplenomegaly may occur. The pulmonary disease is progressive and may lead to respiratory failure within several years.

One third of patients will have a predominantly obstructive pattern, one fourth will have a predominantly restrictive pattern on pulmonary function testing, one third will have reduced carbon monoxide diffusion capacity with normal air flow and lung volumes, and some will have a mix of obstruction and restriction ( Chapter 85 ). A chest radiograph will be normal early in the course but later will show diffuse bilateral infiltrates and hilar lymphadenopathy. Confirmation of beryllium sensitivity is made by the blood beryllium lymphocyte proliferation test. Tissue for histologic analysis from transbronchial or open lung biopsy may confirm the diagnosis.

Treatment

 

 

 

 

 

Treatment involves removing the patient from exposure to beryllium, slowing or halting the progression of the disease with corticosteroids, and providing symptomatic and supportive care.

   Bismuth

 

Epidemiology

 

Bismuth has been used in the treatment of gastrointestinal disorders such as ulcers, diarrhea, and Helicobacter pylori infection. Two forms of bismuth are toxic; lipid-soluble organic compounds (e.g., bismuth subgallate) are neurotoxic, and some water-soluble organic compounds (e.g., bismuth triglycollamate) are nephrotoxic.

Pathobiology

 

Parenterally administered bismuth is distributed throughout the body but concentrates in the kidneys and liver. Elimination is through the kidneys with a terminal elimination half-life of 3 to 10 weeks.

In the blood, bismuth binds to macroglobulins, immunoglobulins, lipoproteins, and haptoglobin. In the kidney, bismuth concentrates in the proximal tubule and causes necrosis. The mechanism of the neurologic effects is unclear.

Clinical Manifestations

 

Chronic exposure to bismuth causes gastrointestinal, dermatologic, renal, and neurologic effects. Gastrointestinal effects include increased salivation, discoloration of the oral mucosa and gums, ulcerative stomatitis, nausea and vomiting, and diarrhea. Dermatologic effects are primarily a generalized rash after parental administration. Renal effects include nephritis, tubular necrosis, and renal failure.

The primary neurologic effect is an encephalopathy developing in two distinct phases. The prodrome lasts up to several months and consists of asthenia, somnolence, depression, anxiety, and sometimes hallucinations. This prodrome is followed by the rapid onset (1 to 2 days) of encephalopathy characterized by confusion progressing to coma or dementia, dysarthria, disturbances of walking and standing, and tremor with myoclonic jerks. Chronic bismuth poisoning is associated with a distinctive electroencephalographic pattern: bilateral low-voltage diffuse beta frequencies that are maximal in the frontal and central regions and that are accentuated during hyperventilation.

The diagnosis of chronic bismuth toxicity is based on the history of exposure and a consistent clinical picture. Blood and urine levels of bismuth may be helpful. In chronic toxicity, the blood bismuth level range is 50 to 1600 μg/L, and the urine level range is 150 to 1250 μg/L. The median blood bismuth levels in patients with bismuth encephalopathy are in the range of 680 to 700 μg/L. In patients taking a bismuth product therapeutically, a blood bismuth level above 50 μg/L is a concern; blood bismuth levels above 100 μg/L are an indication to discontinue bismuth therapy.

Treatment

 

 

 

 

 

Treatment of bismuth toxicity starts with stopping exposure to bismuth. DMPS administration (see Table 20-3 ) has resulted in increased renal excretion of bismuth, but such therapy has not been shown to improve clinical outcomes.

   Chromium

 

The most common forms of chromium in the environment are metallic chromium, trivalent chromium, and hexavalent chromium. Hexavalent chromium is the most toxic form. Trivalent chromium is essential for normal glucose tolerance; chromium picolinate is an alternative dietary supplement.

The trivalent and hexavalent chromiums are the most commonly used forms in industry. Chronic chromium toxicity is essentially an occupational disease related to tanning, metal alloys and electroplating (including surgical metals), photography, dyes, and cement.

Hexavalent chromium is absorbed through the gastrointestinal and respiratory tracts. The other valences are poorly absorbed. Hexavalent chromium is a skin and mucous membrane irritant. In dichromate compounds, hexavalent chromium binds to cellular and nuclear proteins and accumulates in red blood cells and platelets. Reduction of hexavalent to trivalent chromium creates intermediates that cause oxidative damage to DNA. Hexavalent chromium is a human carcinogen (lung cancer), but chromium and trivalent chromium are not classifiable. The Environmental Protection Agency standard for chromium in drinking water is 100 μg/L.

Chronic occupational exposure to high levels of airborne hexavalent chromium has been associated with upper airway irritation (including nasal septum ulceration), bronchospasm, and increased incidence of lung cancer. Repeated exposure to dichromate dust causes conjunctivitis and lacrimation. Dermal effects include irritation and chronic full-thickness ulcers. Chronic ingestion of high doses of chromium picolinate may cause renal impairment. Reference levels of serum chromium are 0.05 to 0.16 μg/L. Treatment of chromium toxicity is symptomatic and supportive.

   Cobalt

 

Cobalt is a naturally occurring element that exists as a metal, as a stable isotope, and as radioactive isotopes. The general public is rarely exposed to the radioactive isotopes (60Co is used in radiation therapy). The metal is in paints, enamels, and alloys used for household appliances, cutting tools, and joint replacements and surgical implants. Cobalt is a normal part of vitamin B12. The average daily North American diet contains 5 to 40 μg of cobalt. Cobalt is absorbed through the gastrointestinal and respiratory tracts, distributed throughout the body, and excreted in the urine. Inhalation of cobalt is associated with obstructive and interstitial pulmonary disease. The interstitial pneumonitis is a fibrosing alveolitis with leukocyte and multinucleated giant cell infiltration ( Chapter 92 ). The process may be an immunoglobulin E–mediated response to cobalt reactivity. Chronic ingestion of or industrial exposure to cobalt produces a cardiomyopathy with pericardial effusions and biventricular heart failure (the beer-drinkers’ cardiomyopathy of the 1960s). Cobalt levels are not useful in the diagnosis or management of chronic cobalt poisoning. The diagnosis is based on a history of exposure and compatible pulmonary findings. Medical evaluation should use standard methods for assessing pulmonary and cardiac function. Treatment consists of removal of the patient from the source of the cobalt and symptomatic supportive care; both N-acetylcysteine and CaNa2EDTA have been used, but there is no definitive clinical evidence of benefit.

   Selenium

 

Selenium is used in the vulcanization of rubber, the manufacture of some red glass, the electronics and semiconductor industry, and in some pharmaceutical products and dandruff shampoos. Selenium is absorbed through the gastrointestinal and respiratory tracts and accumulates primarily in the liver and kidneys. Selenium is cleared from the body in the urine and feces. The mechanism of toxicity of selenium is not clear, but one hypothesis is that it inhibits sulfhydryl enzymes and subsequent reduction in intracellular oxidative reactions.

Chronic exposure to selenium compounds in animals results in hepatotoxicity and decreased growth. In humans, dermal effects include alopecia, abnormal nail formation, and discoloration and decay of the teeth. Chronic high-dose dietary selenium has caused neurologic effects such as paresthesia and paresis. Elevated selenium levels in body fluids have been associated with clinical toxicity. The diagnosis of selenium toxicity relies on identification of a source, compatible clinical findings, and elevated whole blood selenium levels. Whole blood selenium levels vary with dietary intake; people with normal selenium intake (90 to 168 μg/day) have whole-blood selenium levels ranging from 0.143 to 0.211 μg/L. Treatment of a patient with chronic selenium toxicity consists of removing the patient from the selenium source and providing symptomatic and supportive care. Chelating agents are not useful.

   Silver

 

Silver is used widely in photography, electronics, electrical equipment, metal alloys, and antibacterial agents. Silver is ingested in water and foods. Silver toxicity develops after ingestion of at least 25 g of silver during 6 months.

Silver is absorbed through the gastrointestinal tract, the lungs, and the skin. Ingested silver undergoes a significant hepatic first-pass effect. Silver has a high affinity for sulfhydryl groups and other proteins. Inorganic silver salts precipitate intracellularly and in turn are complexed with DNA, RNA, and other proteins; alternatively, ascorbic acid or catecholamines can reduce silver salts to the metallic form. Silver is not carcinogenic. Silver is eliminated primarily in the feces; little is excreted in the urine.

The dermal picture of chronic silver poisoning is argyria, an irreversible blue-gray pigmentation of the skin ( Fig. 20-1 ). In the kidneys, silver is deposited in the basement membrane of the glomerulus; altered renal function is expected but has not been documented clinically. Silver levels in body fluids have not been useful in establishing the diagnosis of chronic silver intoxication. Diagnosis is based on a history of exposure and a compatible clinical picture. Reference levels of serum silver are less than 0.5 μg/L. Treatment of chronic silver intoxication consists of removing the patient from the silver source and providing symptomatic and supportive care. Chelating agents are not useful.

 

 

FIGURE 20-1  A 56-year-old woman (on the left, with a normal person on the right) has had discolored skin since the age of 14 years. At the age of 11 years, the patient was given nose drops of unknown composition for “allergies,” and 3 years later her skin turned gray. She has argyria, and a skin biopsy confirmed silver deposition.  (From Bouts BA: Images in clinical medicine. Argyria. N Engl J Med 1999;340:1554.)

   Uranium

 

Uranium causes toxicity because of its chemical effects or its radiation effects ( Chapter 18 ). Uranium compounds are used in photography and as dyes or fixitives; depleted uranium is used in military equipment. Uranium is poorly absorbed from all exposed sites. Two percent of uranium in drinking water and food is absorbed into the body. Two thirds of the uranium in the body is in the bones, and about 15% is in the liver.

Uranium decays into radium and then into radon, a radioactive gas that seeps into building foundations in particular geographic areas. Although radon is a respiratory carcinogen ( Chapter 201 ), uranium itself is not carcinogenic. The chemical toxicity of uranium affects the kidneys and lungs. Uranium is nephrotoxic but has not led to increased mortality from renal disease in uranium workers. The injury to the lungs is a nonmalignant damage to type II alveolar cells but does not increase mortality from respiratory disease in uranium workers. Treatment of uranium toxicity consists of removing the patient from the uranium source and providing symptomatic and supportive care. Chelators are not recommended.

Although alkalinization of the urine with sodium bicarbonate enhances removal of the uranium molecule from the body, no interventions reduce the effects of chronic uranium toxicity.

   Zinc

 

Zinc is a common element found in air, soil, water, and food. It is widely used in metal alloys, cosmetics, and medications and as an alternative dietary supplement. The oral bioavailability of zinc is variable and depends on the formulation and amount ingested. After ingestion, zinc is concentrated in the liver before being distributed throughout the body. Muscle and bone contain 90% of the total body burden of zinc. High levels of zinc stimulate synthesis of metallothionein in the liver and in the gastrointestinal mucosal cells. Zinc is eliminated from the body primarily through the gastrointestinal tract. Chronic ingestion of zinc in doses as low as 2 mg/kg/day may lead to microcytic anemia secondary to zinc-induced copper deficiency (a result of increased gastrointestinal mucosal cell metallothionein). Other effects of chronic ingestion of high doses of zinc include nausea, vomiting, and abdominal cramping; variable increases in low-density lipoprotein levels and decreases in high-density lipoprotein levels; and impaired white blood cell function. Treatment of chronic zinc toxicity consists of removing the patient from the zinc source and providing symptomatic and supportive care. The use of chelating agents is not recommended.

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