Ebook Current occupational and environmental medicine (5/E): Part 2

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Section IV Occupational and Environmental Exposures

Metals

Richard Lewis, MD, MPH Michael J Kosnett, MD, MPH

The diverse physical properties of metals have resulted in their extensive use

in industry These naturally occurring materials have long been recognizedfor their ability to impart a variety of valuable characteristics to finishedgoods Metals are used in the construction, automotive, aerospace,electronics, glass, and other manufacturing industries Metals are majorsources of pigments and stabilizers for paints and plastics Metals are alsoused as catalysts and intermediates in the chemical and pharmaceuticalindustries Metals may be emitted as contaminants or by-products fromindustrial operations and power generation, and these have become the majorsources of ongoing environmental contamination

Metals are used rarely in their pure form, usually being present in alloys.They also may be bound to organic materials, altering their physicalcharacteristics and potential toxicity Some compounds, such as hydrides andcarbonyls, are highly toxic and may be formed accidentally when the parentmetal reacts with acids Metals may be altered by burning and smelting orafter uptake by biologic systems The chemical structure of the metal ororganometallic compound alters absorption, distribution, and toxicity

Metals exert biologic effects chiefly through the formation of stablecomplexes with sulfhydryl groups, altering the structure and function ofmany proteins and enzyme systems Certain metals, such as zinc, chromium,and manganese, are essential for normal metabolism Others, such as lead,mercury, and arsenic, serve no recognized biologic purpose, raising publichealth concerns owing to their ubiquitous presence in living organisms.Understanding and eliminating health risks from low-level backgroundexposures remains a top priority in environmental health

General population exposure to many metals is related primarily to air,

water, and food contamination Background exposures vary considerablyaround the world owing to natural occurrence in soil and groundwater, aswell as pollution from industrial operations, automotive exhaust, and powergeneration Familiarity with the potential health effects of metals in differentsettings is critical not only for the health and safety professional but also forthe general medical practitioner.

ACUTE METAL TOXICITY

Acute toxicity usually occurs after ingestion of metal-containing compounds

or inhalation of high concentrations of metal dusts or fumes These can arisefrom improperly ventilated burning or welding operations or fromunexpected chemical reactions Home remodeling activities can generate dustfrom paint pigments, particularly lead This and ingestion of paint chips

(pica) are important causes of childhood poisoning Familiarity with the

symptoms of acute heavy metal poisoning, along with an awareness of thepotential sources of exposure, is critical for rapid detection and treatment.The levels of most metals can be measured in blood or urine to confirm thediagnosis and guide therapy

CHRONIC METAL TOXICITY

Research into the health effects of low-level exposure to metals indicates thatphysiologic alterations occur at levels that have been considered safepreviously The evidence for neurotoxicity, circulatory effects,nephrotoxicity, reproductive toxicity, and carcinogenicity at low levels ofexposure continues to grow Regulatory agencies must consider these factors

as they devise exposure standards that provide adequate margins of safety inprotecting long-term population health The challenge for physicians is todifferentiate global public health issues from specific clinical concerns inindividual patients

ARSENIC

ESSENTIALS OF DIAGNOSIS

Acute Effects

• Gastrointestinal distress (nausea, vomiting, diarrhea, abdominal pain)

• Hypotension, metabolic acidosis

• Cardiopulmonary dysfunction (prolonged QT interval, arrhythmias,congestive cardiomyopathy, non-cardiogenic pulmonary edema)

• Anemia and leukopenia

• Sensorimotor peripheral neuropathy

Chronic Effects

• Constitutional (fatigue, malaise)

• Anemia and leukopenia

• Hyperkeratosis and hyperpigmentation

• Sensorimotor peripheral neuropathy

• Peripheral vascular disease

• Cancer of the skin, lung, and bladder

General Considerations

Arsenic is a naturally occurring metalloid that occurs in a variety of chemicalforms and valence states The elemental form, which seldom exists in natureand is of low solubility, is a rare cause of human toxicity Inorganic arsenic isencountered in commerce predominantly as the trivalent (As+3) orpentavalent (As+5) oxides, sulfides, or salts Trivalent forms generally havegreater acute toxicity than the pentavalent species, but in vivo interconversionmay occur, and compounds of both valences are capable of exerting a similarpattern of acute and chronic intoxication Organoarsenicals, which occurnaturally and in many synthetic forms, vary widely in their toxicologicalattributes, from the virtually nontoxic natural compound arsenobetainewidely encountered in seafood, to the highly toxic vesicant warfare agentlewisite (dichloro [2-chlorovinyl] arsine) Arsine, a hydride gas (AsH3) is apotent hemolytic agent

Use

Arsenic is used principally in the United States in the production ofchromated copper arsenide (CCA) wood preservatives for industrialapplications (eg, marine timbers and utility poles); its widespread former use

as a preservative for residential lumber was voluntarily discontinued in 2003.Arsenic is used a minor constituent of metal alloys, such as the hardening oflead in battery grids, bearings, and ammunition, and in the manufacture ofcertain types of glass With the exception of monosodium methanearsonate(MSMA) as an herbicide, virtually all the domestic use of arsenic as apesticide or herbicide has been discontinued High purity arsenic is used inthe manufacture of gallium arsenide chips and circuit boards incorporated inproducts in the electronics, aerospace, and telecommunications sectors.Arsenic trioxide was introduced to the US Pharmacopoeia in 2000 as a drugfor cancer chemotherapy Phenylarsenic compounds are used as feedadditives for poultry and swine, and poultry litter marketed as a soilamendment may contain low levels of soluble arsenic Inorganic arsenic isoccasionally encountered in folk remedies and tonics, particularly some ofAsian origin

Occupational & Environmental Exposure

Occupational exposure to arsenic may occur in the smelting of lead, copper,gold, and other nonferrous metals Readily volatilized arsenic trioxide isconcentrated in flue dust and can be condensed and recovered in a coolingchamber Furnace and flue maintenance operations carry risk of exposure.Arsenic also may be found in fly and bottom ash from coal combustion, andexposure is possible during coal boiler maintenance In the microelectronicsand glass industries, workers may be exposed to arsenic from sourcematerials, finished products, or maintenance operations Arsine gas is used insemiconductor manufacturing and also may be formed accidentally whencompounds or products containing inorganic arsenic come in contact withhydrogen or reducing agents in aqueous solution

General population exposure to inorganic arsenic occurs primarily throughingestion of foodstuffs that contain arsenic as a consequence of its naturalcrustal occurrence or anthropogenic contamination In various parts of theworld, inorganic arsenic of geologic origin may be found in artesian wellwater at concentrations that exceed the U.S Environmental Protection

Agency (EPA) maximum contaminant level of 10 μg/L by one or more orders

of magnitude Arsenic may also leach into groundwater from certain landfills

or surface impoundments containing coal combustion waste Seafoods (fish,mollusks, and seaweeds) may often contain naturally occurring nontoxicorganoarsenicals such as arsenobetaine or various arsenosugars

Absorption, Metabolism, & Excretion

Soluble arsenic compounds are well absorbed after ingestion or inhalation.Percutaneous absorption is limited, but may be of clinical significance afterextensive exposure to concentrated reagents Inorganic arsenic undergoes invivo biomethylation to monomethylarsonic acid (MMA) and dimethylarsinicacid (DMA), which are predominantly excreted, together with residualinorganic arsenic, in the urine Approximately 10–30% appears in the urine

as inorganic arsenic, 10–20% as MMA, and 60–70% as DMA Genetic,dietary, and dose factors appear to influence the extent of biomethylation, and

a relatively higher percentage of MMA in the urine may reflect increasedsusceptibility to arsenic related disease When chronic daily absorption ofinorganic arsenic is less than 1000 μg, approximately two-thirds of theabsorbed dose is excreted in the urine within 2–3 days Arsenic binds tosulfhydryl groups present in keratinized tissue, and small amounts areexcreted by incorporation into the hair and nails Arsenic compounds arebelieved to exert their hazardous effects through multiple modes of action,including inhibition of enzymes vital to cell metabolism, induction ofoxidative stress, and alterations in gene expression and cell signaltransduction Arsine gas uniquely induces massive hemolysis by forming areactive intermediate with oxyhemoglobin that alters transmembrane ion flux

Clinical Findings

A Symptoms and Signs

1 Acute exposure—Acute exposure to several hundred milligrams or more

of a soluble inorganic arsenic salt may result in a constellation ofmultisystemic signs and symptoms that emerge over a period of hours toweeks Early prominent signs include gastrointestinal distress, includingnausea, vomiting, diarrhea, and abdominal pain Diffuse capillary leak mayresult in hypotension, tachycardia, decreased urine output, and shock Central

nervous system findings are highly variable, and range from none to seizuresand encephalopathy If the patient survives the initial phase, a second phasewithin 1 day to 1 week may feature cardiac arrhythmias, congestivecardiomyopathy, and noncardiogenic pulmonary edema A third phase thatemerges 1–4 weeks post ingestion may include anemia and leukopenia, andsensorimotor peripheral neuropathy.

Arsine gas is nonirritating, and inhalation yields no immediate symptoms

A garlic-like odor is occasionally but not invariably noted After a dependent latent interval of 2–24 hours, massive hemolysis may ensue,accompanied by constitutional symptoms of headache, malaise, fever, chills,and gastrointestinal distress Hemoglobinuria imparts a reddish color to theurine, and elevated plasma hemoglobin may result in a bronze discoloration

dose-of the skin Oliguria and acute renal failure, which emerge within 1–3 days,are often major complications

2 Subacute and chronic exposure—Subacute arsenic intoxicationassociated with absorption of weeks to months of >0.05 mg/kg/d may alsoresult in multisystemic effects including fatigue, gastrointestinal symptoms,depressed hemoglobin, liver enzyme elevation, peripheral neuropathy, andprolonged QT interval, possibly associated with ventricular arrhythmias.Chronic arsenic ingestion of >0.01 mg/kg/d over a period of years may result

in the emergence of a distinctive pattern of spotted hyperpigmentation andpalmarplantar hyperkeratosis, a sensory predominant peripheral neuropathy,vascular disease, and noncirrhotic portal hypertension Epidemiological datasuggest a link between chronic arsenic ingestion and diabetes mellitus,hypertension, increased cardiovascular mortality, and nonmalignantrespiratory disease Chronic arsenic inhalation may cause lung cancer, andchronic arsenic ingestion may cause cancer of the skin, lung, and bladder

B Laboratory Findings

Early in the phase of severe acute arsenic poisoning there may be laboratoryevidence of metabolic acidosis and rhabdomyolysis As intoxicationprogresses, there may be anemia and leukopenia, hepatic transaminaseelevation, and QT segment prolongation and arrhythmias on theelectrocardiogram

Measurement of urine arsenic is helpful in confirming recent exposure In

the first 2 to 3 days following acute symptomatic arsenic intoxication, total

urine arsenic concentration is typically ≫ 1000 μg/L and depending on theseverity of poisoning may not return to back ground values for several weeks.Ingestion of seafood, which may contain nontoxic organoarsenicals such asarsenobetaine and arsenosugars, may greatly elevate total urine arsenicconcentration for up to 3 days It may sometimes be useful to have urinearsenic reported as inorganic arsenic plus its primary human metabolitesMMA and DMA—the sum of these three species is usually less than 20 μg/L

in the general population from background dietary and environmentalexposure Segmental analysis of arsenic in the hair and nails may sometimesoffer forensic evidence of elevated arsenic exposure months after urinearsenic concentration has normalized, but values should be interpretedcautiously owing to the potential of external contamination Blood arsenic,which has a highly variable relationship to exposure and is subject to rapidclearance, is rarely of value for clinical diagnosis or biological monitoring

Prevention

Because arsenic is a known human carcinogen, workplace exposure should

be reduced as much as feasible by a program of engineering andadministrative controls, and personal protective equipment Biologicalmonitoring of arsenic in urine may yield information on recent airborne orinhalation exposure to soluble arsenic compounds, but may have limitedutility after inhalation of poorly soluble arsenic aerosols

Treatment

Management of acute arsenic intoxication should combine intensivesupportive care of metabolic acidosis, hypotension, and other cardiovascularderangements with prompt administration of chelating agents Intravenousunithiol (DMPS), the chelating agent of choice, may be of limited availability

in the United States Other useful agents include intramuscular dimercaproland oral succimer (DMSA) Gastric contamination can be considered.Prolonged inpatient support and monitoring may be indicated for initiallysymptomatic patients due to delayed cardiopulmonary and neurologiccomplications Management of chronic arsenic intoxication should focus onremoval from sources of exposure and supportive care Oral chelation withsuccimer can be considered in individuals with high urine arsenic

concentrations, as may folate supplementation in deficient individuals.

Treatment of arsine gas poisoning should focus on vigorous intravenoushydration, possibly supplemented by osmotic diuresis with mannitol, tomaintain urine output and reduce the acute risk of hemoglobinuric renalfailure Elevation of plasma or serum hemoglobin levels of 1.5 g/dL orhigher, and/or signs of renal insufficiency should prompt exchangetransfusion with whole blood Hemodialysis may be indicated for renalfailure, but is not a substitute for the exchange transfusion-mediated removal

of the arsenic-hemoprotein complexes thought to contribute to ongoinghemolysis Chelation is of uncertain value in the management of arsineintoxication

BERYLLIUM

ESSENTIALS OF DIAGNOSIS

Tracheobronchitis, pneumonitis

Granulomatous pulmonary disease

Dermatitis (ulceration and granulomas)

Eye, nose, and throat irritation

Lung cancer

General Considerations

Beryllium is a lightweight gray metal with high tensile strength It isextracted from beryl ore after grinding and heating using electrolyticreduction Bertrandite (4BeO·2SiO2·H2O), although lower in berylliumcontent (0.1–3%), provides a source of acid-soluble beryllium that is moreeasily extracted

Use

The unique properties of beryllium are ideally suited for the production ofhard, corrosion-resistant alloys for use in the aerospace industry Beryllium

alloys (primarily copper) are used in tools, bushings, bearings, and electroniccomponents Beryllium is used in nuclear reactors as a neutron moderator and

a fuel source Beryllium oxide combines high thermal conductivity with highelectrical resistance for use in ceramics, microwave tubes, andsemiconductors Beryllium had been used historically in the manufacture offluorescent and neon lamps, leading to numerous cases of beryllium disease

Occupational & Environmental Exposure

The health risks from exposure to beryllium vary based on the purity of thematerial and the particle size Mining of beryl ore appears to result in arelatively low risk of berylliosis In contrast, the purification and use ofrefined beryllium compounds, particularly beryllium oxide, continues toresult in a substantial risk of sensitization and disease The aerospace,nuclear, electronics, and beryllium alloy industries continue to search formethods of providing adequate worker protection Exposure to minute,ultrafine particles, rather than total mass, may be the key factor in exposureand sensitization Assessment and control of beryllium exposure remainchallenging Current exposure limits may not be adequate, with the mostrecent ACGIH recommendations being 40-fold lower than the OSHA PELand 10 times less than the NIOSH REL

Absorption, Metabolism, & Excretion

Beryllium compounds are poorly absorbed after inhalation, ingestion, or skincontact Beryllium may be retained in the lung or deposited in bone, liver,and spleen Renal excretion is slow but may be used to confirm exposurebecause levels usually are not detectable in nonexposed individuals Thedevelopment of berylliosis does not have a clear dose-response, suggestingthat particle size and individual sensitivity are the key factors for bothsensitization and disease development Pathologically, beryllium toxicity is asystemic disease evidenced by the presence of noncaseating granulomas innumerous tissues, including lung, liver, skin, and lymph nodes

Clinical Findings

A Symptoms and Signs

1 Acute or subacute exposure—Acute or subacute exposure to beryllium

dusts, gas, or fumes has irritant effects on the eyes, mucous membranes, andrespiratory tract Burning eyes, sinus congestion, epistaxis, and sore throatmay be presenting complaints Affected tissues may be swollen, hyperemic,and ulcerated Tracheobronchitis is characterized by cough, chest pain, anddyspnea In severe cases, a chemical pneumonitis may develop, manifested

by tachypnea, hemoptysis, cyanosis, and rales Death has occurred as a result

of pulmonary edema and respiratory failure Acute respiratory and systemicsymptoms may be followed by the development of chronic beryllium disease

2 Chronic exposure—Chronic berylliosis may develop after months oryears of exposure or following a single acute exposure Exertional dyspnea isthe usual presenting complaint, often accompanied by fatigue, weight loss,cough, and chest pain On physical examination, there may be rales,hepatosplenomegaly, lymphadenopathy, and clubbing In long-standingcases, there may be evidence of pulmonary hypertension such as jugularvenous distension, a right ventricular heave, and an accentuated P2 on cardiacauscultation Exacerbations of symptoms may occur following trauma,systemic illness, or pregnancy

After skin contact, beryllium may cause an irritant or allergic dermatitischaracterized by erythema, papules, and vesiculation After penetration of theskin through a cut or abrasion, a granuloma might develop that can ulceratethrough the skin surface Beryllium compounds are considered humancarcinogens, leading to an excess risk of lung cancer

B Laboratory Findings

In cases of acute pneumonitis, there is arterial hypoxemia with diffusepulmonary infiltrates Chronic beryllium disease may present withhypergammaglobulinemia, anemia, elevated liver enzymes, hyperuricemia,and hypercalciuria Pulmonary function studies show either an obstructive orrestrictive pattern The first sign may be a drop in diffusing capacity Incontrast to sarcoidosis, serum angiotensin-converting enzyme levels usuallyare normal Biopsy of affected tissues reveals noncaseating granulomas

While skin testing can confirm hypersensitivity to beryllium, this carries arisk of sensitization Bronchoalveolar lavage (BAL) may demonstratelymphocyte alveolitis with an increase in T cells Radiographic findingsinclude diffuse bilateral nodular or linear infiltrates, often with bilateral hilar

adenopathy Nodular densities suggestive of possible lung cancer need to beassessed carefully.

The beryllium lymphocyte proliferation test (BeLPT) confirmssensitization Two positive or one positive and one borderline test areconsidered adequate to confirm sensitization The management of exposedworkers with borderline BeLPT results is challenging, often requiringsimultaneous testing at two laboratories and periodic follow-up until theresults are confirmed as either positive or negative

Prevention

While standard exposure control measures appear to be effective in theprocessing of beryl ores, prevention of berylliosis in other industry sectorsremains a challenge There is evidence that risk of beryllium sensitization andchronic increased in workers with a glutamic acid at position E69 on HLA-DPB1 Standard medical surveillance should include periodic pulmonaryfunction testing, including the diffusing capacity BeLPT testing also should

be conducted The frequency should be adjusted to the experience of theoperation, recognizing that sensitization can occur shortly after first exposure

Treatment

Persons with beryllium disease should be removed from exposure Treatment

of acute pneumonitis should include supplemental oxygen andcorticosteroids Chronic beryllium disease also may respond to steroids,starting with prednisone, 60 mg orally daily, and tapering slowly Skinlesions should be cleansed thoroughly and treated with topical steroids Themanagement of asymptomatic workers with a positive BeLPT test remainscontroversial

Prognosis

Berylliosis is a chronic disease that may persist and progress even aftercessation of exposure Prevention and early detection are critical

CADMIUM

Use

Cadmium compounds are used extensively in electroplating Cadmiumimparts corrosion resistance to steel, iron, and a variety of other materials foruse in automotive parts, aircraft, marine equipment, and industrial machinery.Cadmium alloys are used in high-speed bearings, solder, and jewelry.Cadmium sulfides and selenides are used as pigments in rubber, inks,plastics, paints, textiles, and ceramics, particularly where heat stability andalkali resistance are desirable Nickel-cadmium batteries are used in motorvehicles and rechargeable household appliances Cadmium is also used inphotoelectric cells and in semiconductors

Occupational & Environmental Exposure

The recovery and refining of cadmium compounds are associated withpotential exposure to high levels of both dusts and fume Workers also mayhave exposure to cadmium in the smelting of zinc, lead, and copper.Cadmium plating is used to impart a protective coating for aerospace andother applications Workers may be exposed to cadmium mist from platingbaths, as well as to fine cadmium dust when handling or machining platedparts Cadmium compounds are used in the manufacture of batteries, paints,and plastics Welders and brazers may be exposed to cadmium oxide fumeswhen working with cadmium-containing silver solders

Nonoccupational exposure occurs primarily through dietary intake Liverand meat by-products, shellfish, and vegetables are potential sources ofintake Air and water contamination may be significant in areas surroundingzinc smelters Irrigation of rice paddies with contaminated water in Japan led

to an epidemic of osteoporosis in postmenopausal women (Itai-Itai disease)

in the 1940s, demonstrating that environmental contamination can lead tosignificant health impact Food also may become contaminated when stored

in ceramic containers that have been glazed with cadmium The tobacco plantaccumulates environmental cadmium, and cigarette smoke is an importantsource of chronic cadmium exposure in humans

Absorption, Metabolism, & Excretion

Cadmium is absorbed primarily through inhalation or ingestion Skinabsorption is negligible under ordinary circumstances After inhalation, 10–40% may be absorbed, depending on particle size and chemical composition.Gastrointestinal absorption is usually 5% but may be increased in thepresence of iron, protein, calcium, or zinc deficiencies

Absorbed cadmium is bound to plasma proteins Cadmium accumulates inthe liver and kidneys, where intracellular binding to metallothionein protectsagainst cellular damage Liver stores are released slowly and taken up by thekidney There is a gradual increase in the body burden of cadmium, peaking

at age 60 years

Excretion is primarily renal, with a biologic half-life of 8–30 years.Transient peaks in urinary excretion also may occur after short-term, high-dose exposure Renal excretion of cadmium increases after chronic exposure

because of impaired proximal tubular reabsorption, a manifestation ofcadmium-induced nephrotoxicity.

Clinical Findings

A Symptoms and Signs

1 Acute exposure—Acute inhalation of cadmium oxide fume has resulted inindustrial fatalities After a delay of several hours, victims complained of sorethroat, headache, myalgias, nausea, and a metallic taste Fever, cough,dyspnea, and chest tightness progress to a fulminant chemical pneumonitisand death from respiratory failure Hepatic and renal injury also may occurfollowing acute exposure Ingestion of cadmium compounds results innausea, vomiting, headache, abdominal pain, liver injury, and acute renalfailure

2 Chronic exposure—The most frequent manifestation of chronic exposure

to cadmium is proteinuria Initially, there is increased excretion of molecular-weight proteins, such as β1- and β2-microglobulins Withcontinued exposure, this can progress to Fanconi syndrome, withaminoaciduria, glycosuria, hypercalciuria, and phosphaturia Cadmium-induced renal failure may be difficult to distinguish from diabeticnephropathy Renal tubular dysfunction can result in nephrolithiasis andosteomalacia Bone pain and pathologic fractures may occur owing to renalcalcium and phosphorus loss and impaired synthesis of vitamin D Chronicinhalation of cadmium dusts and fumes also may result in pulmonary fibrosisand emphysema Other effects that have been reported include anosmia andanemia Cadmium is potentially neurotoxic and also may cause testicularinjury Cadmium is a human carcinogen and is associated with an excess risk

low-of lung cancer and prostate cancer There are associations between cadmiumexposure and tumors at other locations including kidney, breast, and prostate

B Laboratory Findings

1 Acute inhalation—Evaluation of acute inhalations should include anarterial blood gas evaluation, a chest radiograph, spirometry, and assessment

of renal and hepatic function Hypoxemia, diffuse pulmonary infiltrates, and

a reduction in forced expiratory volume in 1 second (FEV1), forced vitalcapacity (FVC), and diffusing capacity for carbon monoxide indicate acute

cadmium oxide exposure and impending respiratory failure In subacutecases, bronchopneumonia may develop Normal blood and urine cadmiumlevels are 1 μg/L and 1 μg/g of creatinine, respectively After acute cadmiumfume inhalation, these may rise as high as 3 and 0.36 mg/L.

2 Chronic exposure—Workers exposed to cadmium should participate inperiodic biologic monitoring and medical examinations The biologicmonitoring should include urine and blood cadmium levels, as well asmeasurement of urinary β2-microglobulin levels Tables 30–1 and 30–2summarize the requirements of the programs for cadmium-exposed workers

in the United States

Table 30–1. Biologic monitoring program for cadmium

Table 30–2. Medical examination for cadmium workers

Medical and occupational history

Focusing on cadmium exposure; smoking; renal, cardiovascular,

musculoskeletal, and respiratory conditions; reproductive concerns; use

of nephrotoxic medications, recent physical exercise, recent febrile

illnesses

Physical examination

Blood pressure, respiratory system, genitourinary system, prostate

examination (men older than age 40 years), respirator medical clearance

Diagnostic testing

Pulmonary function testing

Chest radiograph

Complete blood count

Blood urea nitrogen, creatinine

Urinalysis, urinary protein measurements

β1- and β2-microglobulin levels are a sensitive indicator of cadmiumnephrotoxicity, although exercise, febrile illness, nephrotoxic medications,and other kidney disorders also may affect these tests A loss of sense ofsmell, mild anemia, and airway obstruction also may be observed in workerswith chronic exposure

Biologic monitoring should focus on the minimizing cadmium exposure toprevent proteinuria Urine cadmium levels should be kept below 3 μg/g ofcreatinine to prevent chronic renal damage Because of the long biologicalhalf-life of cadmium, the ongoing protection of workers who have hadsignificant past exposure is difficult using biologic monitoring

Cadmium is persistent in the environment and may contaminate water andfood supplies International research continues to evaluate the possible role ofenvironmental cadmium exposure in cardiovascular, bone, and renal diseases

Treatment

Persons who have suffered acute inhalation of cadmium oxide fumes should

be thoroughly evaluated for evidence of acute lung injury Admission to thehospital for observation is indicated because respiratory support may berequired In severe acute poisoning, chelation with calcium disodium edetate(CaNa2 EDTA) may enhance cadmium excretion Renal function should bemonitored closely Dimercaprol should not be used Individuals withevidence of chronic cadmium toxicity should be removed from furtherexposure.

CHROMIUM

ESSENTIALS OF DIAGNOSIS

Sinusitis, nasal septum perforation

Allergic and irritant dermatitis, skin ulcers

Respiratory irritation, bronchitis, asthma

Lung cancer

General Considerations

Chromium is a hard, brittle gray metal that is widely distributed as chromite(FeOCr2O3) or ferrochromium Chromite is extracted through bothunderground and open-cast mining Chromium metal is produced throughreduction of chromic oxide with aluminum Chromates are produced by hightemperature roasting of chromite in an oxidizing atmosphere The valencestate is a critical factor in determining the toxicity of chromium compounds.Hexavalent chromium [Cr(VI)] is the most toxic and is carcinogenic Incontrast, trivalent chromium [Cr(III)] is an essential element for normalglucose metabolism in humans

Use

Chrome plating is used on automotive parts, household appliances, tools, andmachinery, where the coating imparts corrosion resistance and a shiny,decorative finish Chromium-iron alloys alone or with the addition of nickel

or manganese produce a variety of durable, high-strength stainless steels.Chromium compounds also provide heat resistance in refractory materials.Chromate pigments and preservatives are added to paints, dyes, textiles,rubber, plastics, and inks Chrome-based implantable orthopedic devices areused for joint replacement The radioisotope 56Cr is used in nuclear medicine

to label erythrocytes

Occupational & Environmental Exposure

Mining and crushing operations result in exposure primarily to chromicoxide The greatest occupational hazards historically have been in chromateproduction, where exposure to Cr(VI) resulted in a high incidence of lungcancer Exposure to chromium fumes occurs in the production of stainlesssteel Arc welding of stainless steel also results in exposure to chromiumcompounds Electroplaters are exposed to chromic acid mists Erosion of thenasal septum was a common finding in chrome platers before theimplementation of proper ventilation Workers also may be exposed tochromates through their use in the paint, textile, leather, glass, and rubberindustries and in lithography, printing, and photography Certain cementshave a high chromium content Chromium is found in low concentrations inwater, urban air, and a variety of foods Chromium in jewelry is a commoncause of skin allergies

Absorption, Metabolism, & Excretion

Chromium compounds may be absorbed after ingestion, inhalation, or skincontact The soluble Cr(VI) forms are absorbed much more readily than theinsoluble trivalent forms Cr(VI) readily enters cells, where it is converted toCr(III) Intracellular Cr(III) binds to proteins and nucleic acids IngestedCr(III) is absorbed less readily and crosses into cells much more slowly.Chromium generally does not accumulate in tissues, although inhaledinsoluble forms may remain in the lung Excretion is primarily renal

Clinical Findings

A Symptoms and Signs

Acute exposure to high concentrations of chromic acid or chromates will

cause immediate irritation of the eye, nose, throat, and respiratory tract.Chronic exposure may cause ulceration, bleeding, and erosion of the nasalseptum Cough, chest pain, and dyspnea may indicate exposure to irritantlevels of soluble chromium compounds or the development of chromium-induced asthma.

Dermatologic manifestations are common in chromium workers

Penetration of the skin will cause painless erosive ulceration (chrome holes)

with delayed healing These occur commonly on the fingers, knuckles, andforearms Chromates are both skin irritants and allergens Localizederythematous or vesicular lesions at points of contact or generalizedeczematous dermatitis, particularly of the hands, should suggest sensitization.Ingestion of chromium compounds has caused nausea, vomiting,abdominal pain, and prostration Death is a result of uremia

Chromium is a known human carcinogen Workers involved in chromateproduction, chrome plating, and chrome alloy work all have been found tohave an increased incidence of lung cancer The carcinogenicity of chromiumcompounds is attributed to Cr(VI)

B Laboratory Findings

With massive exposure, there will be evidence of renal and hepatic damage.Proteinuria and hematuria precede anuria and uremia A reduction in theFEV1:FVC ratio on spirometry may be seen after acute irritant exposure or inworkers with chromium-induced asthma Skin allergy can be confirmed bypatch testing Persistent cough, hemoptysis, or a mass lesion on chestradiograph in a chromium worker should prompt a thorough evaluation forpossible lung cancer

Prevention

Reduction of exposure to Cr(VI) will reduce the respiratory and nasalcomplications Surveillance for nasal irritation or septal perforation willidentify high-risk jobs to direct exposure-control efforts Avoidance of skincontact—particularly contact with damaged or inflamed skin—will reducethe risk of developing chrome ulcers or skin sensitization Prompt evaluationfor skin sensitization will prevent the development of severe or chronicdermatitis

Exposure to Cr(VI) should be reduced to the lowest feasible levels toreduce the risk of lung cancer Chromium workers also should be encouraged

to stop smoking Biologic monitoring of urine chromium levels may beuseful as an assessment of recent exposure Exposure to 0.05 mg/m3 ofCr(VI) in air will result in levels of 30–50 μg/g of creatinine at the end of theworkweek

Treatment

Persons who have suffered acute inhalation injury should be admitted to thehospital for observation Supplemental oxygen and bronchodilators may berequired Careful attention to fluid and electrolyte balance is indicated in thesetting of acute renal injury Chromium-induced nasal and skin ulcerationsshould be treated with a 10% ointment of CaNa2 EDTA and an imperviousdressing with frequent application to prevent formation of persistent,insoluble Cr(III) Persons who develop chromium respiratory or skin allergyshould be removed from further exposure if they cannot be protectedadequately

LEAD (INORGANIC)

ESSENTIALS OF DIAGNOSIS

Acute Effects

• Central nervous system (fatigue, headache, encephalopathy)

• Gastrointestinal (constipation, abdominal pain)

• Hematological (hemolytic; hypochromic, normocytic, or microcyticanemia)

Chronic Effects

• Constitutional (fatigue, malaise, insomnia, anorexia, weight loss,

decreased libido, arthralgias, myalgias)

• Cardiovascular (hypertension; increased cardiovascular morbidity andmortality)

• Hematologic (normochromic or microcytic anemia)

• Central nervous system (impaired concentration and cognition,

headache, diminished visual-motor coordination, tremor,

encephalopathy)

• Peripheral motor neuropathy

• Renal (chronic interstitial fibrosis; hyperuricemia and gout)

• Reproductive and developmental (impaired growth and neurobehavioraldevelopment; adverse reproductive outcomes, altered sperm formationand function)

General Considerations

Lead is a soft, malleable, blue-gray metal characterized by high density andcorrosion resistance The ores of commercial interest include the sulfide(galena), the carbonate (cerussite), and the sulfate (anglesite) Lead isconcentrated through flotation and smelted in a three-step process: blending,sintering, and furnace reduction Raw lead is further refined to removecopper, arsenic, antimony, zinc, tin, bismuth, and other contaminants

Lead serves no useful biologic function in humans Lead exerts its toxiceffects by interfering with the action of essential cations (eg, calcium, zinc,iron) and macromolecules (enzymes, receptors, membranes, transcriptionfactors) in cells throughout the body This may result in alterations inmitochondrial and cellular membranes, neurotransmitter synthesis andfunction, cellular redox status (oxidative stress), nucleotide metabolism, andendocrine signaling Because these myriad biochemical actions impact cellsthroughout the body, subclinical or overt impacts in multiple organ systemsare a hallmark of lead toxicity

Use

Lead is among the most extensively recycled of any commodity metal.Secondary smelting accounts for approximately 80% of US domestic leadconsumption, approximately 85% of which is used in the production of leadacid batteries Although lead acid batteries are used primarily in theautomotive industry, their use in uninterrupted power supplies for computersand telecommunications is increasing worldwide, especially in thedeveloping world Additional uses of lead include ammunition; pigments,

glass, and ceramics; alloys in steel, brass, bronze, and solder; and sheet leadfor construction, industrial tanks and vessels, and radiation shielding (Table30–3) Global production and consumption of lead has been increasing overthe past decade, and this trend is expected to continue.

Table 30–3. Lead sources in occupations and industries

Ammunition/explosives production

Artisanal gold mining

Automotive repair shops

Battery manufacturing and recycling

Brass, bronze, copper, or lead foundries

Bridge, tunnel and elevated highway/subway construction

Cable/wire stripping, splicing or production

Ceramic manufacturing

Firing range work

Glass recycling, stained glass and glass manufacturing

Home renovation/restoration

Lead abatement

Lead production or smelting

Machining or grinding lead alloys

Manufacturing and installation of plumbing components

Manufacturing of industrial machinery and equipment

Metal scrap yards and other recycling operations

Motor vehicle parts and accessories (including radiator repair)

Occupations using firearms

Pipe dope (lubricants)

Plastics manufacturing

Pottery or ceramic manufacturing

Production and use of chemical preparations

Radiation shielding

Rubber manufacturing

Sandblasting, sanding, scraping, burning, or disturbing lead paint

Use of lead based paints

Welding or torch-cutting painted metal

Occupational & Environmental Exposure

According to data collected by the 41 states that participate in the NIOSHAdult Blood Lead Epidemiology and Surveillance (ABLES) program,approximately 95% of all elevated blood lead levels among adults in theUnited States are work-related Industry subsectors with the highest numbers

of lead-exposed workers have included battery manufacturing, secondarysmelting and refining of nonferrous metals, and painting and paper hanging.Although most lead exposure occurs in manufacturing sectors, constructionwork disproportionately contributes cases with very high blood lead levels(≥40 ug/dL) Construction workers may sporadically encounter high leadexposure during demolition, sandblasting, sanding, or mechanical or torchcutting of structures or components fabricated with lead or covered with leadpaint or coatings Inhalation of lead dust or fume has been the predominantpathway of occupational lead exposure, but incidental ingestion of dust may

be significant in some cases Prominent nonoccupational exposures to lead byadults include shooting firearms; remodeling, renovating, or painting;retained bullets (gunshot wounds); and lead casting (Table 30–4)

Table 30–4. Hobbies, activities and other sources that may result in leadexposure

Beauty products such as kohl eye makeup, certain hair dyes

Electronics with lead solder

Folk remedies or traditional medicines

Furniture refinishing

Glassblowing with leaded glass

Hunting and target shooting

Imported children’s jewelry

Jewelry making with lead solder

Liquor distillation (moonshine)

Pottery and ceramic production with lead glazes and paints

Print making and other fine arts

Remodeling/renovating homes built before 1978

Retention of lead bullets or shrapnel

Stained glass craftwork and painting on stained glass

In the United States, children are predominantly exposed to lead byingestion of deteriorated residential lead based paint applied many years inthe past, and lead contaminated house dust and soil Children may also beexposed to lead dust carried home on the contaminated clothing of adultswith occupational exposure, and lead in consumer products The latter mayinclude certain imported home remedies and cosmetics, imported candies orfoods, toys, imported or handmade lead-glazed pottery or tableware, andinexpensive children’s jewelry Corrosion of lead in older plumbing mayincrease the lead content of tap water Historical automotive emissions fromleaded gasoline continues to contaminate certain soils, particularly near majorroadways, and there is ongoing exposure to airborne or settled lead emittedfrom active or inactive point sources such as smelters, metal working ormining sites Air lead emissions have declined drastically (>99%) in theUnited States over the past four decades, and the largest overall source ofemission nationwide is piston engine aircraft operating on leaded aviationgasoline

Absorption, Metabolism, & Excretion

Inhalation and ingestion are the primary routes of lead absorption Airborneparticle size influences overall transfer of inhaled lead to the blood, because

as particles become larger they have an tendency to deposit in the upperairway and be translocated to the gut, rather than to deposit in the lowerairway and undergo direct respiratory absorption Toxicokinetic modeling ofempiric data suggests that in workplace settings, approximately 35–40% ofinhaled lead is ultimately absorbed to the bloodstream The extent to which

ingested lead is absorbed to the blood is influenced in part by particlesolubility (soluble particles undergo greater absorption), the mass of leadingested, and the extent of coingestion with liquids or solid food (food in thegut decreases absorption) An estimated 15% of ingested soluble lead isabsorbed in adults, compared to approximately 40–50% in young children.Iron-deficiency and low calcium diets may increase gastrointestinalabsorption.

In the blood, approximately 99% of lead is bound to erythrocytes and 1%

is present in the plasma Lead is initially distributed to soft tissues such as thebone marrow, brain, kidney, liver, muscle, and gonads; subsequently to thesubperiosteal surface of bone; and ultimately to bone matrix Lead alsocrosses the placenta and poses a potential risk to the fetus The clearance oflead from the body follows a multicompartment model composedpredominantly of the blood and soft tissues with a half-life of 1–2 months andbone with a half-life of years to decades Approximately 70% of leadexcretion is via the urine, with lesser amounts eliminated through the bile,skin, hair, nails, sweat, and breast milk The fraction not undergoing promptexcretion, approximately half of the absorbed lead, may be incorporated intothe skeleton, the site of greater than 90% of the body lead burden in mostadults In patients with a high burden of lead in bone, slow redistribution tothe blood may elevate blood lead concentrations for years after exposureceases Skeletal lead mobilization may be accelerated during conditionsassociated with increased bone turnover, such as hyperthyroidism,immobilization osteoporosis, and pregnancy and lactation

Clinical Findings

A Symptoms and Signs

1 Acute exposure— Acute symptomatic lead intoxication is now a rareoccurrence, and usually requires several days or weeks of intense exposure

In occupational settings, this may be associated with exposure to lead oxidefume or high concentrations of lead in dust Children may present with acutelead intoxication following ingestion of lead present in paint chips, toys,ornaments or other small objects Both adults and children may sustain acutemassive exposure from contaminated food, beverage, or folk medicines Thesigns and symptoms are usually neurological—ranging from headache toataxia to diminished sensorium or consciousness and convulsions

(encephalopathy)—and/or gastrointestinal—nausea, constipation, and crampyabdominal pain (lead colic) In children with encephalopathy, there mayantecedent or concurrent evidence of decreased visual acuity or abnormalities

of the third or sixth cranial nerves

The diagnosis of acute lead intoxication may be challenging, anddepending on the presenting signs and symptoms it has sometimes beenmisdiagnosed as appendicitis, peptic ulcer, biliary colic, pancreatitis, pelvicinflammatory disease, or meningitis Subacute presentations featuringanorexia, malaise, myalgias, arthralgias, headache, and intermittentabdominal cramps have been mistaken for a flu-like viral illness

2 Chronic exposure—Chronic symptomatic lead intoxication ischaracterized by the insidious onset of dose-dependent multisystemic signsand symptoms Constitutional findings may include fatigue, malaise,arthralgias, myalgias, anorexia, insomnia, loss of libido, irritability, anddepressed mood Neurologic symptoms may begin with decrements inconcentration and headache, and possibly progress after high exposure tofrank encephalopathy Tremor may occur Gastrointestinal disturbances mayinclude constipation and crampy abdominal pain Months to years of highdose lead exposure (eg, blood lead concentrations >80 μg/dL) may beassociated with a predominantly motor peripheral neuropathy, andnephropathy, the latter characterized by interstitial fibrosis andnephrosclerosis Chronic renal effects also include hyperuricemia and gout.Adverse reproductive effects associated with high lead exposure includespontaneous abortion or stillbirth in females, and diminished or aberrantsperm production in males An impact of low-level exposure on reproductiveoutcomes such as preterm delivery, low birth weight, and spontaneousabortion has been inconsistently observed in epidemiological studies

The subclinical effects of chronic lead exposure are of considerable publichealth concern Low-level lead exposure has deleterious effects on theneurocognitive development of the fetus and young child, and no blood leadthreshold for this impact has been identified In adults, chronic lead exposureassociated with blood lead concentrations in the range of 10–25 μg/dL is anestablished risk factor for elevated blood pressure, and exposure of thismagnitude has been linked to increased cardiovascular mortality in largeepidemiological studies

B Laboratory Findings

Whole blood lead concentration is the most common and useful laboratorytest to confirm exposure Lead in blood is a reasonable reflection of the leadcontent of most soft tissues However, because blood lead is influenced byrecent exogenous exposure as well as by redistribution of skeletal lead stores,knowledge of the temporal pattern of exposure is invaluable when evaluatingblood lead measurement in workplace biomonitoring The geometric meanblood lead concentration for the general United States population in 2009–

2010 was 1.1 μg/dL (95th percentile 3.3 μg/dL) Noninvasive K x-rayfluorescence measurement of lead in bone, a biomarker of long-termcumulative lead exposure, is used predominantly as a research tool.Measurement of lead in urine following a dose of a chelating agent (chelationchallenge testing) correlates satisfactorily in most cases with blood lead testresults, and is seldom indicated in clinical practice

An elevation in erythrocyte protoporphyrin (often measured as zincprotoporphyrin or ZPP) reflects lead-induced inhibition of heme synthesis.Because there is a time lag of several weeks associated with lead-inducedelevation in ZPP, the finding of a blood lead of ≥30 μg/dL with no concurrentincrease in ZPP suggests that the lead exposure was of recent onset

Acute high-dose lead exposure may induce a hemolytic anemia, (oranemia with basophilic stippling if exposure has been subacute) Hepaticaminotransferases may be elevated Chronic lead intoxication may result in ahypochromic anemia that is either normocytic or microcytic Elevated BUNand serum creatinine may reflect transient azotemia associated with acute orsubacute high-dose lead exposure, or the irreversible renal insufficiency ofchronic lead nephropathy Radiographically, abdominal x-rays may showopacities consistent with recent lead ingestion, and a head CT scan revealingcerebral edema may aid in the diagnosis of lead encephalopathy

Prevention

Prevention of occupational overexposure to lead can be accomplishedthrough a careful program of product substitution, engineering controls,personal protective equipment, and work practices such as assiduous handwashing and post-shift showering Current OSHA lead standards that requiremedical removal from elevated workplace lead exposure when blood leadlevels exceed 50 or 60 μg/dL were enacted several decades ago and offer

insufficient protection An expert panel in 2007 recommended that removal

be initiated for a single blood lead level greater than 30 μg/dL, or when twosuccessive blood lead levels measured over a 4-week interval are ≥20 μg/dL.The longer-term goal should be for workers to maintain blood lead levels <10μg/ dL (Table 30–5)

Table 30–5. Medical surveillance recommendations for lead-exposed

workers

In 2010, the US Centers for Disease Control and Prevention issuedguidelines for the identification and management of lead exposure inpregnant and lactating women that recommended prompt action to reducelead exposure in women with prenatal blood lead levels ≥5 μg/dL, andmedical removal from workplace exposure of any woman with a prenatalblood lead level of ≥10 μg/dL

If workplace blood lead concentrations are maintained below 20 μg/dL, itmay be sufficient to implement a streamlined medical surveillance regimen inwhich laboratory testing is limited to blood lead measurements every 6

months if blood lead levels remain <10 μg/dL, and every 3 months if bloodlead levels are 10–19 μg/dL Additional recommended program elementsinclude annual measurement of blood pressure, an annual questionnaireregarding medical conditions (such as renal insufficiency) that might increasethe risk of lead-related adverse health effects, and periodic worker educationregarding the nature of lead hazards and controls.

In 2012, CDC recommended parental education, environmentalinvestigation, and additional medical monitoring for all children with bloodlead concentrations >5 μg/dL EPA regulations effective since 2010 requirecontractors performing renovation, repair, and painting projects that disturblead-based paint in pre-1978 residences and child-occupied facilities toundergo certification and to adhere to specific work practices to prevent leadcontamination

Treatment

The essential first step in the management of lead intoxication isidentification and elimination of the sources of overexposure Chelatingagents, such as parenteral calcium disodium EDTA (calcium versenate) ororal dimercaptosuccinic acid (DMSA, succimer), decrease lead concentration

in the blood and certain tissues, and greatly accelerate urinary lead excretion.However, there are no randomized placebo-controlled trials of chelation thatindicate it improves the therapeutic outcome of patients In general, chelation

in adults should be reserved for those with markedly elevated blood leadconcentrations (eg, >80–100 μg/dL), or possibly symptomatic individualswith blood lead concentration >50 μg/dL The CDC recommends chelation ofchildren with blood lead concentrations ≥45 μg/dL Chelation ofasymptomatic children or adults with low blood lead concentrations is notrecommended Chelation, as well as the supportive care and decontaminationrequired for symptomatic patients, should be conducted under the guidance of

an experienced specialist in occupational medicine or medical toxicology.Adjunctive measures include treatment of coexisting iron deficiency anemia,and provision of adequate dietary calcium

MANGANESE

ESSENTIALS OF DIAGNOSIS

Manganese-induced parkinsonism

Behavioral changes, psychosis

Respiratory symptoms and disease

General Considerations

Manganese is a brittle gray metal that is abundant in soils and sediments Themost important source of manganese for commercial use is manganesedioxide, occurring as pyrolusite Manganese is an essential trace element inhumans with an average daily requirement of 2–5 mg for adults

Use

Ferromanganese, an iron alloy containing more than 80% manganese metal,

is used in steel production Manganese serves as a depolarizer in dry-cellbatteries and an oxidizing agent for chemical syntheses Manganese is used inthe manufacture of matches, paints, and pesticides (Maneb) The manganesecarbonyls, particularly methylcyclopentadienyl manganese tricarbonyl(MMT), have been used as antiknock agents in fuel and as sources ofmanganese in the electronics industry

Occupational & Environmental Exposure

Exposure to manganese dioxide occurs in the mining, smelting, and refining

of manganese ores Manganese exposure also occurs near crushing operationsand reduction furnaces engaged in the production of alloys and steel Theseoperations historically had the highest levels of exposure and the greatest riskfor manganese toxicity

Exposures may occur in battery production, chemicals plants, and theelectronics industry Workers engaged in the manufacture of fuels containingMMT may have respiratory or skin contact with this highly toxic liquid.Combustion of manganese-containing fuels results in environmental release

of manganese oxides Welding rods and steel alloys are other sources ofoccupational manganese exposure

Absorption, Metabolism, & Excretion

Manganese fume is readily absorbed after inhalation There also may beuptake via the olfactory nerve Larger particles are ingested after mucociliaryclearance from the lungs Gastrointestinal absorption generally is low (10%)but may be increased in persons who are iron deficient MMT may beabsorbed after ingestion, inhalation, or skin contact

Manganese is excreted primarily in the bile The biologic half-life ofmanganese is approximately 30 hours Blood, urine, and hair levels areelevated in exposed workers, but individual results do not correlate withsymptoms or toxicity Variations in manganese or iron homeostasis mayaccount for variable individual susceptibility to toxicity

Clinical Findings

A Symptoms and Signs

1 Acute exposure—Dermal and respiratory exposure to MMT results inslight burning of the skin followed by headache, a metallic taste, nausea,diarrhea, dyspnea, and chest pain Acute overexposure to MMT can causechemical pneumonitis and hepatic and renal toxicity

2 Chronic exposure—Industrial exposure to manganese can result inchronic nervous system damage The earliest manifestations are fatigue,headache, apathy, and behavioral changes Episodes of excitability,

garrulousness, and sexual arousal have been termed manganese psychosis.

With continued exposure, there is development of a clinical syndrome that issimilar to idiopathic parkinsonism, with slow speech, masked facies,bradykinesia, gait dysfunction, and micrographia Tremor is less common inmanganism Salivation, sweating, and vasomotor disturbances also mayoccur Whether low levels of manganese exposure increase the risk ofparkinsonism continues to be a subject of ongoing research

Inhalation of manganese dust has been associated with increasedrespiratory symptoms and susceptibility to respiratory infections

B Laboratory Findings

Laboratory findings usually are normal Minor decreases in leukocyte and redblood cell counts may be seen Liver enzyme elevations also have been

reported T1-weighted images on magnetic resonance imaging (MRI)demonstrate high signal changes in the globus pallidus indicating manganeseaccumulation Measurement of elevated urine or blood manganese levelsconfirms exposure These measurements can discriminate exposed fromnonexposed groups but do not correlate well with individual exposure or thedegree of toxicity.

Prevention

Manganese exposure should be reduced by the use of closed systems, localexhaust ventilation, and respiratory protection Dermal and respiratoryexposure to MMT should be prevented through the use of proper personalprotective equipment Medical surveillance should focus on the nervoussystem and the respiratory system Careful neurologic examinations andpulmonary function testing should be performed routinely on all exposedworkers Workers with exposure to MMT also should have periodicassessment of respiratory, liver, and kidney function

Treatment

Workers suspected of having manganese-induced parkinsonism should beremoved from exposure Manganese-induced symptoms are resistant totreatment with levodopa, a factor that distinguishes this from idiopathicParkinson’s disease Pneumonia, bronchitis, and asthma should be treatedwith appropriate therapy while the worker is removed from exposure

After skin contact with MMT, the affected areas should be cleansedimmediately to reduce skin absorption Workers who develop respiratorysymptoms after inhalation of MMT should be admitted to the hospital forobservation Liver and kidney function should be monitored

MERCURY

ESSENTIALS OF DIAGNOSIS

Inorganic Mercury

• Acute respiratory distress

• Tremor

• Erethism (shyness, emotional lability)

• Proteinuria, renal failure

Organic Mercury (Alkyl Mercury Compounds)

Use

Elemental mercury is used in control instruments, tubes, rectifiers,thermometers, barometers, batteries, and electrical devices Mercury in brinecells catalyzes the electrolytic production of chlorine Historical use of alkylmercury compounds (methyl mercury and ethyl mercury) as grain fumigantscaused serious human poisoning Mercury is used in plating, jewelry,tanning, and taxidermy Use in the felt industry in the nineteenth century led

to extensive poisoning (“mad as a hatter”) Mercury dental amalgams remain

an important source of low-level exposure, along with vaccines containing

the mercury preservative thiomersal While both clearly contribute tobackground population exposures, the health impact of these uses remainsuncertain Mercury has also been used in skin lightening creams leading toexposure and toxicity.

Occupational & Environmental Exposure

Workers involved in the extraction and recovery of mercury are at high riskfor exposure to mercury vapor Maintenance work on furnaces and flues isanother source of exposure Chloralkali workers can have significantexposure from contamination if workplace hygiene is not maintained

Mercury is being phased out of medical equipment, although health careworkers still may be exposed from damaged or broken equipment or pastworkplace contamination Dentists and dental technicians may have short-term peak exposures during certain dental procedures Workers may beexposed to alkyl mercury compounds during the production and application

of organic mercury fungicides or the use of these agents in paints andplastics

Two serious epidemics of organic mercury poisoning occurred owing toenvironmental contamination of food sources Release of mercury wastesfrom a chemical plant into Minamata Bay in Japan led to accumulation of

methyl mercury in seafood Minamata disease resulted in neurologic

impairment and birth defects in thousands of the affected area residents.Distribution of grain contaminated with organic mercury fungicides similarlypoisoned over 50,000 persons in Iraq These clear demonstrations of thetoxicity of organic mercury continue to drive regulations to reduce mercuryemissions and lower the acceptable levels of mercury in fish and seafood

Absorption, Metabolism, & Excretion

Elemental mercury is efficiently absorbed after the inhalation but notingestion Soluble mercurial salts (Hg2+) and aryl mercury compounds havesimilar uptake Alkyl mercury compounds are absorbed readily through allroutes, including skin contact

Inorganic and aryl mercury compounds are distributed to many tissues,although the brain and kidney are the primary target organs There they bind

to sulfhydryl groups and interfere with numerous cellular enzyme systems

Metallothionein, a protein rich in sulfhydryl groups, binds mercury and exerts

a protective effect in the kidney Alkyl mercury in the bloodstream is taken

up rapidly by red blood cells and also accumulates in brain tissue

Both organic and elemental mercury compounds readily cross the placentaand are secreted in breast milk Peak exposures to both organic and inorganicmercury compounds are more hazardous because of the intense effects on thecentral nervous system Mercury compounds are eliminated slowly in theurine, feces, saliva, and sweat The average half-life is 60 days for inorganicmercury and 70 days for alkyl mercury compounds Mercury also may bemeasured in the hair and nails

Clinical Findings

A Symptoms and Signs

1 Inorganic mercury—Inhalation of high concentrations of mercury vapor

or salts causes cough and dyspnea Inflammation of the oral cavity andgastrointestinal complaints occur shortly after exposure, followed by achemical pneumonitis Renal injury is a particular concern after exposure tomercuric chloride and presents as an initial diuresis followed by proteinuriaand oliguric renal failure After recovery from the acute illness, neurologicsymptoms similar to those seen with chronic overexposure may develop.Chronic exposure to inorganic mercury compounds primarily affects thenervous system Neuropsychiatric manifestations include changes inpersonality, shyness, anxiety, memory loss, and emotional lability Tremor is

an early sign of neurotoxicity Initially, the tremor is fine and occurs at rest,progressing with further exposure to an intention tremor interrupted by coarsejerking movements A head tremor and skeletal ataxia also may occur Asensory peripheral neuropathy usually is present with distal paresthesias.Hallucinations and dementia are serious late manifestations

Other reported findings after include salivation, gingivitis, and dentalerosions A bluish linear pigmentation may be present on the teeth or gums.Reddish brown pigmentation of the lens may be apparent on slit-lampexamination Excessive sweating and an eczematous skin eruption also may

be present

2 Organic mercury—Exposure to alkyl mercury compounds results in thedelayed, insidious onset of progressive nervous system damage that may be

fatal The earliest symptoms are of numbness and tingling of the extremitiesand lips Loss of motor coordination follows, with gait ataxia, tremor, andloss of fine movement Constriction of the visual fields, central hearing loss,muscular rigidity, and spasticity occur with exaggerated deep tendon reflexes.Behavioral changes and intellectual impairment may be prominent.Erythroderma, desquamation, and other skin rashes may be present Renaldisease is rare Neurotoxicity in infants exposed in utero in the Minamata Bayepidemic resembled cerebral palsy.

B Laboratory Findings

After acute inhalation, there may be hypoxemia and diffuse infiltrates onchest x-ray Proteinuria indicates renal injury The earliest manifestations ofrenal effects are increased excretion of low-molecular-weight proteins,

including N-acetyl-β-glucosaminidase, β2-microglobulin, and retinol-bindingprotein

Measurement of mercury in blood and urine will confirm the diagnosis.Gross renal or neurologic manifestations are unusual unless urine mercurylevels exceed 500 μg/g of creatinine Subtle nervous system effects have beendetected in workers with levels of 50–150 μg/g of creatinine, and early renaleffects (low-molecular-weight proteinuria with normal renal function) havebeen detected when urine mercury levels chronically exceed 50 μg/g ofcreatinine Normal concentrations in nonexposed individuals are less than0.01 mg/L in whole blood and less than 10 μg/g of creatinine in urine.Substantial seafood consumption may result in high blood levels with lowurine levels A high ratio of whole blood mercury to plasma mercury suggestsalkyl mercury intoxication Hair and nail levels may be used to documentexposure but do not correlate well with toxicity

Prevention

Awareness of the constant hazard of mercury vapor exposure along withproper handling of materials and meticulous attention to workplace hygienewill reduce potential exposures Use of proper ventilation and respiratoryprotection is required in all operations that use mercury compounds Specialattention should focus on maintenance workers Care in the handling anddisposal of mercury compounds will prevent inadvertent contamination of the

workplace Control of industrial emissions will prevent contamination ofwaterways and seafood.

Medical surveillance of mercury-exposed workers should include a carefulhistory and neurologic examination as well as periodic urinalyses Table 30–6provides a sample biologic monitoring program Urine levels fluctuate, andperiodic monitoring or group monitoring is more representative of ongoingexposure Greater accuracy may be obtained by adjusting to urine creatinine

Table 30–6. Biologic monitoring program for mercury.a

Treatment

After acute exposure to mercury, prompt treatment with dimercaprol (5mg/kg intramuscularly) should be instituted Respiratory distress and renalfailure should be treated appropriately Succimer and dimercaptosuccinic acidare also effective and are indicated for organic mercury intoxication.Individuals manifesting symptoms of chronic mercury toxicity should beremoved from further exposure The decision to give treatment in such casesdepends on the severity of the symptoms and whether evidence of neurologic

or renal toxicity is present Chronic mercury poisoning also may respond tochelation therapy The chronic neurologic sequelae of alkyl mercurypoisoning are irreversible.

Use

Thallium sulfate was used as a medicinal in the treatment of syphilis,gonorrhea, gout, and tuberculosis in the nineteenth century Abandonedbecause of its toxicity, it enjoyed a brief resurgence as a depilatory in the1920s [201Tl]Cl is currently used in myocardial imaging for the diagnosis ofcardiac ischemia

Thallium salts have been used extensively as rodenticides in the form of

impregnated grain (Thalgrain) and pastes (Zelio) Numerous accidental andsuicidal poisonings led to the banning of these compounds in the UnitedStates in 1972 Currently, thallium is finding increasing uses in themanufacture of electronic components, optical lenses, imitation jewelry, dyes,and pigments.

Occupational & Environmental Exposure

At highest risk for exposure are those engaged in the production of thalliumsalt derivatives In addition, workers in the electronics and optical industrieshave potential exposure to thallium compounds Thallium exposure can occur

at smelters, particularly in the maintenance and cleaning of ducts and flues.Environmental exposure can occur in the vicinity of smelting operationsthrough air and water contamination Consumption of contaminated grainremains an important cause of accidental poisoning Thallium chloride hasbeen found in potassium chloride salt substitutes

Metabolism & Mechanism of Action

Thallium—and especially its soluble salts—is absorbed readily through thegastrointestinal tract, skin, and respiratory system Ingestion of 0.5–1 g may

be lethal Elimination is slow and occurs through intestinal and renalsecretion in a ratio of 2:1 Thallium behaves much like potassium and bindsavidly to several enzyme systems, including Na+, K+-ATPase Thalliumbinds to sulfhydryl groups and interferes with cellular respiration and proteinsynthesis Binding to riboflavin may contribute to its neurotoxicity

Clinical Findings

A Symptoms and Signs

1 Acute exposure—Gastrointestinal symptoms predominate early andinclude pain, nausea, vomiting, hemorrhage, and diarrhea Cardiacabnormalities include tachycardia and hypertension Neurologicmanifestations usually begin with pain, hyperesthesia, and hyperreflexia inthe lower extremities This may progress rapidly to areflexia, hypesthesia,and paralysis depending on the amount ingested Ataxia, agitation,hallucinations, and coma may occur in severe cases Alopecia, primarily of