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4 Chromium Toxicity

Environmental ALERT…

Chromium (III) is an essential nutrient, which can be toxic in large doses.

The toxicity of chromium compounds depends on the oxidation state of the metal.

Occupational exposure to chromium (VI) has been associated with increased incidence of lung cancer.

The efficacy of chelation therapy in chromium poisoning has not been proven.

This monograph is one in a series of self-instructional publications designed to increase the primary care provider’s knowledge of hazardous substances in the environment and to aid in the evaluation of potentially exposed patients. The Agency for Toxic Substances and Disease Registry (ATSDR) and the Centers for Disease Control (CDC) designate this continuing medical education activity for 1 credit hour in Category 1 of the Physician’s Recognition Award of the American Medical Association and 0.1 continuing education units for other health professionals. See pages 21 to 23 for further information.

Guest Contributor:

Vikas Kapil, DO, MPH

Guest Editor:

James Keogh, MD, MPH

Peer Reviewers:

Charles Becker, MD; Jonathan Borak, MD; Joseph Cannella, MD;

Bernard Goldstein, MD; Alan Hall, MD;

Richard J.Jackson, MD, MPH; Jonathan Rodnick, MD;

Robert Wheater, MS; Brian Wummer, MD

U.S. DEPARTMENT OF HEALTH & HUMAN SERVICES

Public Health Service

Agency for Toxic Substances and Disease Registry



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Environmental Medicine: Integrating a Missing Element into Medical Education 4 Chromium Toxicity Environmental ALERT… Chromium (III) is an essential nutrient, which can be toxic in large doses. The toxicity of chromium compounds depends on the oxidation state of the metal. Occupational exposure to chromium (VI) has been associated with increased incidence of lung cancer. The efficacy of chelation therapy in chromium poisoning has not been proven. This monograph is one in a series of self-instructional publications designed to increase the primary care provider’s knowledge of hazardous substances in the environment and to aid in the evaluation of potentially exposed patients. The Agency for Toxic Substances and Disease Registry (ATSDR) and the Centers for Disease Control (CDC) designate this continuing medical education activity for 1 credit hour in Category 1 of the Physician’s Recognition Award of the American Medical Association and 0.1 continuing education units for other health professionals. See pages 21 to 23 for further information. Guest Contributor: Vikas Kapil, DO, MPH Guest Editor: James Keogh, MD, MPH Peer Reviewers: Charles Becker, MD; Jonathan Borak, MD; Joseph Cannella, MD; Bernard Goldstein, MD; Alan Hall, MD; Richard J.Jackson, MD, MPH; Jonathan Rodnick, MD; Robert Wheater, MS; Brian Wummer, MD U.S. DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service Agency for Toxic Substances and Disease Registry

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Environmental Medicine: Integrating a Missing Element into Medical Education Case Study Chronic skin ulcers and respiratory irritation in a 35-year-old handyman A 35-year-old man is seen at your family practice office near a large Midwestern city with complaints of “allergies” and sores on his hands and arms. Over the past 2 to 3 months, the patient has noticed the onset of “runny nose,” “sinus drainage,” dry cough, and occasional nosebleeds (both nares intermittently). There is no prior history of allergies. He has also had occasional nausea and is concerned because the sores and minor skin cuts on his hands do not seem to heal. The patient denies having fever, chills, dyspnea, or change in bowel or bladder habits, and he has not noticed excessive thirst or easy bruising. He recently began experiencing loss of appetite and weight loss without dieting. With the exception of the complaints mentioned, review of systems is otherwise unremarkable. The patient has used various over-the-counter remedies for his respiratory problems without relief. He did, however, note significant improvement in symptoms when he visited his sister in Chicago for 5 weeks at the end of summer. Medical history reveals only usual childhood diseases. Other than OTC decongestants, he is taking no medications. He denies use of illicit drugs, but admits to occasional social use of alcohol. For the last 16 years he has smoked 1 pack of low-tar cigarettes a day. The patient has been employed as a mathematics teacher for 13 years; summers are usually spent in self-employment as a handyman. His hobbies include reading and tennis. Two years ago he moved into a ranch-style house located several hundred yards from a small manufacturing plant; a small pond intervenes. The home has central air conditioning and gas heat; it is supplied with well water and uses a septic sewage system. Four months ago the patient began digging up the sewage system to make repairs. It was shortly after he began digging that he first noticed the sores on his hands and forearms. Physical examination reveals an alert white male with skin lesions on the exposed areas of the forearms and hands; edema of the hands is present. The dermal lesions include dermatitis and small circular areas with shallow ulcerated centers. ENT examination is unremarkable, and chest examination reveals a few scattered rhonchi that clear with coughing. His liver is slightly enlarged and tender to palpation. Cardiovascular, genito-urinary, rectal, and neurologic examinations are unremarkable. Initial laboratory findings include evidence of 2+ proteinuria and hematuria, and slightly elevated bilirubin, SGOT (AST), and SGPT (ALT). Scrapings of the dermal lesions, done with potassium hydroxide (KOH) preparation, show no fungal elements or signs of infestation on microscopic examination. A nasal smear for eosinophils is within normal limits. (a) Formulate an active problem list for this patient. _________________________________________________________________ (b) What clues indicate this case may have an environmental etiology? _________________________________________________________________ (c) What further information will you seek before making a diagnosis? _________________________________________________________________ (d) What treatment will you recommend? _________________________________________________________________ Answers to the Pretest can be found on page 19.

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Environmental Medicine: Integrating a Missing Element into Medical Education Exposure Pathways ❑ Chromium exists in three common stable valence states; in order of generally increasing toxicity, they are chromium (0), (III), and (VI). ❑ Chromium is released to air primarily by combustion processes and metallurgical industries. ❑ Nonoccupational sources of chromium include contaminated soil, air, and water. Chromium is a hard, steel-gray metal highly resistant to oxidation even at high temperatures. It is the sixth most abundant element in the earth’s crust, where it is combined with iron and oxygen in the form of chromite ore. The Soviet Union, South Africa, Albania, and Zimbabwe together account for 75% of world chromite production. Chromite ore has not been mined in the United States since 1961; in 1985 this country became completely dependent on importation for its primary chromium supply. Chromium is used in three basic industries: metallurgical, chemical, and refractory (heat-resistant applications). In the metallurgical industry, chromium is an important component of stainless steels and various metal alloys. Metal joint prostheses made of chromium alloys are widely employed in clinical orthopedics. In the chemical industry, chromium is used primarily in paint pigments (chromium compounds can be red, yellow, orange, and green), chrome plating, leather tanning, and wood treatment. Smaller amounts are used in drilling muds, water treatment, catalysts, safety matches, copy machine toners, corrosion inhibitors, photographic chemicals, and magnetic tapes. Refractory uses of chromium include magnesite-chrome firebrick for metallurgical furnace linings and granular chromite for various other heat-resistant applications. Chromium exists in a series of oxidation states from −2 valence to +6; the most important stable states are 0 (elemental metal), +3 (trivalent), and +6 (hexavalent). Chromium in chromite ore is in the trivalent state, whereas industrial processes also produce the elemental metal and hexavalent chromium. The health effects of chromium are at least partially related to the valence state of the metal at the time of exposure. Trivalent (Cr [III]) and hexavalent (Cr [VI]) compounds are thought to be the most biologically significant. Cr (III) is an essential dietary mineral in low doses, whereas certain compounds of Cr (VI) appear to be carcinogenic. Insufficient evidence exists to determine if Cr (III) or chromium metal can be human carcinogens. Cr (III) and Cr (VI) are released to the environment primarily from stationary point sources resulting from human activities. Of the total atmospheric chromium emissions in the United States, approximately 64% is due to chromium (III) from fuel combustion (residential, commercial, and industrial) and from steel production; about 32% is due to chromium (VI) from chemical manufacture, chrome plating, and industrial cooling towers using chromate chemicals as rust inhibitors. A recent U.S. Environmental Protection Agency (EPA) report estimates that in the United States about 2840 metric tons of total chromium are emitted annually into the atmosphere (compared to approximately 110,000 tons of chromium metal produced each year).

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Environmental Medicine: Integrating a Missing Element into Medical Education Electroplating, leather tanning, and textile industries release relatively large amounts of chromium in surface waters. Solid wastes from chromate-processing facilities, when disposed of improperly in landfills, can be sources of contamination for groundwater, where the chromium residence time may be several years. The content of chromium in tap water in U.S. households is from 0.4 to 8.0 micrograms per liter (µg/L), which is slightly increased through use of stainless steel plumbing materials. (EPA’s maximum contaminant level for chromium in drinking water is currently 50 µg/L.) In the 1960s and 1970s, chromium-containing slag was used as landfill in residential, commercial, and recreational settings in over 100 locations in Hudson County, New Jersey. This fill contains chromium in carcinogenic forms and in concentrations acutely toxic in certain circumstances. Community exposure from this fill occurs in a variety of ways. Wind erosion of the soil can make slag particles airborne, increasing the opportunity for inhalation of chromium, and chromium compounds leached by rainwater have been found to migrate through cracks in soil, asphalt roadways, and masonry walls, forming high-content chromium crystals on their surfaces. In soil and roadways, these particles may be eroded by wind and foot traffic and carried as chromium-laden dust into homes and workplaces. Children playing in areas where the slag was used as fill may also be exposed through skin contact with chromium-contaminated dust, dirt, and puddles. Less significant environmental sources of chromium include road dust contaminated by emissions of chromium-based catalytic converters or erosion products of asbestos brake linings, cement dust, tobacco smoke, and foodstuffs. Cigarettes contain 0.24 to 14.6 milligram chromium/kilogram, but neither the amount of chromium inhaled nor the chemical form is known. Processing and refining removes much of the normally small amount of chromium naturally present in foods. Environmental and occupational sources of chromium exposure include the following: Environmental Airborne emissions from chemical plants incineration facilities Effluents from chemical plants Contaminated landfill Cement dust Road dust from catalytic converter erosion asbestos brake lining erosion Tobacco smoke Occupational Welding of alloys steel Leather tanning (soluble Cr [III]) Chrome electroplating (soluble Cr [VI]) Chrome alloy production Textile manufacturing Paints/Pigments (insoluble Cr [VI]) Photoengraving Copier servicing

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Environmental Medicine: Integrating a Missing Element into Medical Education (1) On further questioning, the patient described in the case study relates that when he had reached several feet in depth while digging to repair the sewage system, he noticed an oozing from the ground of sometimes yellowish, sometimes greenish, water; this persisted throughout the several weeks of digging. The nearby pond, which is murky, also has a generally yellow tint with small areas of greenish color at times. Suspecting an environmental link, you contact the local health department. Extremely high levels of chromium are found in the pond water, and the investigators inform you that the nearby plant is electroplating auto parts with chromium. Discuss all sources and pathways by which this patient may be exposed to chromium. _________________________________________________________________ _________________________________________________________________ _________________________________________________________________ Who’s at Risk ❑ Workers in industries producing and using chromium are at greatest risk of chromium’s adverse effects. ❑ Risk assessment is currently underway for residents living on landfill derived from chromium-containing solid wastes. Workers in industries using chromium, especially stainless steel welding, chromate production, chrome plating, and chrome pigment industries, where exposure is primarily to Cr (VI), are at increased risk of chromium’s effects. An estimated 175,000 workers may be exposed to Cr (VI) in the workplace on a regular basis; the number is much greater if exposure to other valence states of chromium are also considered. In many occupations, exposure is to both Cr (III) and Cr (VI) as soluble and insoluble materials. Residents near chromate production facilities may be exposed to higher-than-background levels of chromium (VI). There is also concern that residents whose homes have been built on landfill using slag from smelters or chromate-producing facilities may be exposed to chromium through inhalation and dermal contact. Groundwater contamination may increase exposure in persons using well water as a drinking water source. Coal and oil combustion contribute an estimated 1723 metric tons of chromium per year in atmospheric emissions; however, only 0.2% of this chromium is Cr (VI). In contrast, chrome-plating sources are estimated to contribute 700 metric tons of chromium per year to atmospheric pollution, but 100% is believed to be Cr (VI).

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Environmental Medicine: Integrating a Missing Element into Medical Education Despite air and water contamination from industrial pollution, no adverse health effects have been documented in persons residing near chromium point sources or in persons drinking chromium-contaminated water. (2) Besides the patient, who in the case study may be at risk of chromium exposure? _________________________________________________________________ _________________________________________________________________ Biologic Fate ❑ Cr (VI) is better absorbed from the lungs, gut, and skin than Cr (III). ❑ After absorption, Cr (VI) is reduced to Cr (III). ❑ The difference in bioavailability and bioactivity between Cr (III) and Cr (VI) may account for the differences in toxicity. ❑ Only Cr (III) is excreted, primarily in the urine. The entry routes of chromium into the human body are inhalation, ingestion, and dermal absorption. Occupational exposure generally occurs through inhalation and dermal contact, while the general population is exposed most often by the oral route through chromium content in soil, food, and water. Rates of chromium uptake from the gastrointestinal tract are relatively low and depend on a number of factors, including valence state (with Cr [VI] more readily absorbed than Cr [III]), the chemical form (with organic chromium more readily absorbed than inorganic chromium), the water solubility of the compound, and gastrointestinal transit time. In humans and animals, less than 1% of inorganic Cr (III) and about 10% of inorganic Cr (VI) is absorbed from the gut; the latter amount is slightly higher in a fasting state. The percentage of chromium absorption from the lungs cannot be estimated. Data from a few animal experiments indicate that with equal solubility, Cr (VI) compounds are absorbed more readily than Cr (III) compounds, probably because Cr (VI) readily penetrates cell membranes. Data from volunteers and indirect evidence from

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Environmental Medicine: Integrating a Missing Element into Medical Education occupational studies indicate that absorption of certain Cr (VI) compounds can occur through intact skin. After entering the body from an exogenous source, Cr (III) does not readily cross cell membranes, but binds directly to transform, an iron-transporting protein in the plasma. In contrast, Cr (VI) after absorption is rapidly taken up by erythrocytes and reduced to Cr (III) inside the cell. Regardless of the source, Cr (III) is widely distributed in the body and accounts for most of the chromium in plasma or tissues. The greatest uptake of Cr (III) as a protein complex is by bone marrow, lungs, lymph nodes, spleen, kidney, and liver. Autopsies reveal chromium levels in the lungs are consistently higher than levels in other organs. Excretion of chromium occurs primarily via the urine with no major retention in organs. In humans, the kidney excretes about 60% of an absorbed Cr (VI) dose in the form of Cr (III) within 8 hours of ingestion. Approximately 10% of an absorbed dose is eliminated by biliary excretion, and smaller amounts are excreted in hair, nails, milk, and sweat. Clearance from plasma is generally rapid (within hours), while elimination from tissues is slower (half-life of several days). In volunteers, administered doses of Cr (VI) were more rapidly eliminated than those of Cr (III). (3) Analysis of blood and urine specimens from the patient described in the case study reveals an elevated Cr (III) serum and urine concentration. Assuming the patient was exposed only to chromium (VI), explain the presence of chromium (III) in each of these body fluids. _________________________________________________________________ _________________________________________________________________ _________________________________________________________________ _________________________________________________________________

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Environmental Medicine: Integrating a Missing Element into Medical Education Physiologic Effects ❑ Cr (III) is an essential trace mineral in human nutrition. ❑ Because Cr (VI) is a powerful oxidizing agent, exposure can cause irritating and corrosive effects. ❑ The target organ of inhaled chromium is the lung; the kidneys, liver, skin, and immune system may also be affected. Chromium (III), an essential dietary element, plays a role in maintaining normal metabolism of glucose, fat, and cholesterol. Chromium’s nutritional role has not been thoroughly delineated, but it appears to potentiate insulin action, probably in the form of glucose tolerance factor (GTF). The estimated safe and adequate daily intake of chromium for adults is in the range of 50 to 200 micrograms a day, although data are insufficient to establish a recommended daily allowance. Dietary chromium deficiency is relatively uncommon; most cases occur in persons with special problems such as total parenteral nutrition, diabetes, or malnutrition. Chromium deficiency is characterized by glucose intolerance, glycosuria, hypercholesterolemia, decreased longevity, decreased sperm counts, and impaired fertility. In one patient receiving total parenteral nutrition, a peripheral neuropathy was corrected after chromium supplementation. Major factors governing the toxicity of chromium compounds are oxidation state and solubility. Chromium (VI) compounds, which are powerful oxidizing agents and, as such, tend to be irritating and corrosive, appear to be much more toxic systemically than chromium (III) compounds, given similar amounts and solubilities. Although mechanisms of biologic interaction are uncertain, this differing toxicity may be related to the ease with which Cr (VI) can pass through cell membranes and its subsequent intracellular reduction to reactive intermediates. Skin Effects ❑ Severe dermatitis and skin ulcers can result from contact with Cr (VI) salts. ❑ Chromium compounds can be sensitizers as well as irritants. Chromic acid, dichromates, and other Cr (VI) compounds are not only powerful skin irritants but can also be corrosive. On broken skin, a penetrating round ulcer may develop. Common sites for these persistent ulcers (“chrome holes”) include the nail root, knuckles and finger webs, back of the hands, and forearms. The characteristic chrome sore begins as a papule, forming an ulcer with raised hard edges. Ulcers may penetrate deep into soft tissue or become the site of secondary infection, but are not known to lead to malignancy. The progression to ulceration is generally painless, suggesting toxicity to peripheral sensory nerves. The lesions heal slowly and may persist for months.

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Environmental Medicine: Integrating a Missing Element into Medical Education At concentrations below those resulting in irritation, skin sensitivity is the most common effect after exposure to chromium compounds, especially Cr (VI) compounds. Up to 20% of chromium workers develop dermatitis. Allergic dermatitis with eczema has been reported in printers, cement workers, metal workers, painters, and leather tanners. Data suggest that a Cr (III)-protein complex is responsible for the allergic reaction, with Cr (III) acting as the hapten. Respiratory Tract Effects ❑ When inhaled, chromium (VI) is a respiratory tract irritant and may cause pulmonary sensitization. ❑ Chronic chromium inhalation increases the risk of lung cancer. Human occupational experience clearly indicates that, when inhaled, chromium (VI) is a respiratory tract irritant, resulting in airway irritation, airway obstruction, and possibly lung cancer. Dose, exposure duration, and the specific compound involved determine chromium’s effects. Pulmonary irritant effects after prolonged inhalation of chromate (VI) dust may include chronic irritation, congestion and hyperemia, chronic rhinitis, polyps of the upper respiratory tract, tracheobronchitis, and chronic pharyngitis. X-ray abnormalities reflect enlargement of the hilar region and lymph nodes, increased peribronchial and perivascular lung markings, and adhesions of the diaphragm. Consistent associations have been found between employment in the primary chromium industries and the risk for respiratory cancer (see Carcinogenic Effects section). Pulmonary sensitization resulting in an asthmatic response is more common from Cr (VI) than from Cr (III). A delayed anaphylactoid reaction was reported in a male worker occupationally exposed to chromium vapors from chromium (VI) trioxide baths and chromium fumes from steel welding. A subsequent inhalation challenge with sodium chromate resulted in a reaction including late onset urticaria, angioedema, and bronchospasm accompanied by tripling of plasma histamine levels. Many cases of nasal mucosa injury (inflamed mucosa, ulcerated septum, perforated septum) have been reported in workers exposed to Cr (VI) in chrome-plating plants and tanneries. A 1983 study of 43 chrome-plating plants in Sweden, where workers were exposed almost exclusively to chromic (VI) acid, revealed that all workers with nasal mucosa ulceration or perforation were periodically exposed to at least 20 µg/m3 when working near the plating baths. (The current U.S. permissible exposure level in the workplace for chromates and chromic acid is 100 µg/m3 over an 8-hour period.) The period of exposure for workers experiencing nasal mucosal ulceration varied from 5 months to 10 years.

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Environmental Medicine: Integrating a Missing Element into Medical Education Renal Effects ❑ Low-dose, chronic chromium exposures generally cause only transient renal effects. ❑ Acute Cr (VI) exposure may result in renal tubular necrosis. Studies of welders and chromium platers have found that workers with higher levels of exposure to airborne chromium (typically greater than 20 µg/m3) show damage to renal tubules. Adverse renal effects have been reported in humans after inhalation, ingestion, and dermal exposure to chromium. Renal effects in animals occurred only after parenteral administration of large doses. Although glomerular injury has been noted in chromium workers, the predominant renal injury is tubular, with low doses acting specifically on the proximal convoluted tubules. Low-dose, chronic chromium exposure typically results only in transient renal effects. Elevated urinary ß2-microglobulin levels (an indicator of renal tubular damage) have been found in chrome platers, and higher levels generally have been observed in younger persons exposed to higher Cr (VI) concentrations. However, in a study of tannery workers (Cr [III] exposure) whose duration of employment ranged from 1 month to 30 years, urinary ß2-microglobulin levels were within normal limits, even though urinary chromium levels clearly indicated chromium exposure. A suggested urinary threshold for nephrotoxic effects is 15 µg chromium/g creatinine. Hepatic Effects ❑ Chromium (VI) may cause mild to moderate liver abnormalities. Acute chromium exposure can result in hepatic necrosis. External chromic acid burns over 20% of a worker’s body resulted in severe liver damage and acute renal failure. Limited data indicate that chronic inhalation of chromium compounds also can cause hepatic effects. Acute hepatitis with jaundice was reported in a woman who had been employed for 5 years at a chromium-plating factory. Tests revealed large amounts of urinary chromium, and liver biopsy showed abnormalities. Three coworkers exposed to chromic acid mists from the plating baths for 1 to 4 years also had mild to moderate liver abnormalities, as determined by liver function tests and liver biopsies. Carcinogenic Effects ❑ Occupational exposure to Cr (VI) has long been associated with increased lung cancer mortality. ❑ Latency for chromium-induced lung cancer is greater than 20 years; exposure duration may be as short as 2 years. Epidemiologic studies of occupational cohorts exposed to chromium aerosols provide clear evidence of carcinogenicity. In one key epidemiologic study involving workers at a chromate production plant who had worked for more than 1 year from 1931 to 1949, the percentage of deaths due to lung cancer was 18.2%; 1.2% was expected. For the 322 workers first employed from 1931 to 1937, the percentage of deaths due to lung cancer was close to 60%, with a latency period of approximately 30 years. Studies of workers in the chromium pigment, chrome-plating, and ferrochromium industries

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Environmental Medicine: Integrating a Missing Element into Medical Education also suggest a statistically significant association between worker exposure to chromium and lung cancer. Increased lung cancer mortality has been associated with occupational exposures as short as two or three years. On the basis of these and other studies, EPA and the International Agency for Research on Cancer (IARC) have classified inhaled chromium (VI) as a known human carcinogen. Chromium (III) has not been classified as a human carcinogen by the National Toxicology Program, EPA, or IARC. Although epidemiologic evidence strongly points to the hexavalent form of chromium as the agent in carcinogenesis, solubility and other characteristics of chromium compounds may be important in determining cancer risk. Data from animal studies do not resolve the issues of identities and potencies of various chromium-containing compounds as respiratory carcinogens. No chromium compound has been unequivocally shown to cause a significant increase in the number of neoplasms in experimental animals after exposure by natural routes (inhalation, ingestion, or dermal absorption), unless the animals were exposed until dead. (Standard protocols for animal experiments involve termination after 24 months.) However, intratracheal instillation, intrabronchial implantation, or injection of various chromium-containing compounds have produced tumors at the site of application in some cases. No cancers, other than lung cancer, are associated with occupational chromium exposure. All pathologic cell types have occurred in chromium-induced lung cancers; however, small cell and poorly differentiated cancers predominate. Findings of some epidemiologic studies and animal experiments suggest chromium is also associated with nonrespiratory cancers, but the evidence is insufficient to consider the nonrespiratory cancers to be of a causal nature. Reproductive and Developmental Effects ❑ Data indicate chromium is teratogenic in animals. ❑ Potential reproductive effects of chromium in humans have not been adequately investigated. Chromium (III) is an essential element that is transported to the developing fetus. Less than 0.5% of Cr (III) was found to cross the placenta in mice when the chromium was administered as an inorganic salt, but 20% to 25% was found in litters when chromium was administered in a biologically active form, brewer’s yeast. Adverse developmental effects in animals include cleft palate, hydrocephalus, delayed ossification, edema, and incomplete neural tube closure. Data are unavailable implicating chromium in adverse human reproductive or developmental effects.

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Environmental Medicine: Integrating a Missing Element into Medical Education (4) Could chromium toxicity account for the symptoms experienced by the patient described in the case study? Explain. _________________________________________________________________ _________________________________________________________________ _________________________________________________________________ (5) Is the patient at increased risk of chromium-induced lung cancer? _________________________________________________________________ _________________________________________________________________ _________________________________________________________________ Clinical Evaluation History and Physical Examination ❑ If chromium exposure is suspected, the respiratory system, kidneys, liver, and skin should be evaluated. Often there are no clear diagnostic clues in chromium-poisoned patients. A thorough history is therefore critical in evaluating a potentially exposed person. The patient’s recent activities are important when health effects other than cancer are the major concern. Occupation, location of residence and workplace in relation to industrial facilities or hazardous waste sites, and source of drinking water supply should be investigated. In patients with known chronic chromium exposure, the physical examination should include evaluation of the respiratory system (if inhalation is involved), kidneys, liver, and skin.

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Environmental Medicine: Integrating a Missing Element into Medical Education Signs and Symptoms Acute Exposure ❑ Ingestion of a lethal dose of chromate may result in cardiovascular collapse due to severe hypovolemia. ❑ Sublethal doses of chromate may lead to renal and hepatic necrosis 1 to 4 days after ingestion. Severe exposures to chromium compounds are rarely occupational or environmental, but are usually accidental or suicidal. Short-term, high-level exposure to Cr (VI) produces irritation at the site of contact including ulcers of the skin, irritation of the nasal mucosa, perforation of the nasal septum, and irritation of the gastrointestinal tract. Less is known about the acute toxicity of Cr (III) compounds, although they are generally believed to be less toxic. About 1 gram of potassium dichromate (IV) is considered a lethal dose. Persons who ingested 5 grams or more experienced gastrointestinal bleeding, massive fluid loss, and death within 12 hours after ingestion. When the ingested dose was 2 grams or less, renal tubular necrosis and diffuse hepatic necrosis resulted and contributed to death in some cases. Typically, the kidney and liver effects develop 1 to 4 days after ingestion of a sublethal dose. Other symptoms of acute Cr (VI) ingestion include vertigo, thirst, abdominal pain, and vomiting. Oliguria, anuria, shock, convulsions, coma, and death can ensue. Gastrointestinal hemorrhage and coagulopathy may also occur. Acute chromium poisonings are often fatal regardless of the therapy employed. Dermal contact with Cr (VI) compounds can result in severe systemic toxicity. Antiscabies ointment containing Cr (VI) resulted in necrosis of skin at application sites, nausea, vomiting, shock, coma, and death. In one case, severe nephritis and death followed cauterization of an open wound with chromium (VI) oxide, and an occupational fatality was described after an accident in which a worker was burned on the arms and trunk with hot potassium dichromate. Both of these cases involved broken rather than intact skin. Chronic Exposure ❑ In occupational settings, the most commonly reported effects of chronic chromium exposure are contact dermatitis, and irritation and ulceration of the nasal mucosa. ❑ Less common are reports of hepatic and renal damage and pulmonary effects. ❑ Lung cancer is a potential long-term effect of chronic Cr (VI) exposure. Repeated skin contact with chromium dusts may lead to incapacitating eczematous dermatitis with edema. Chromate dusts may also produce irritation of the conjunctiva and mucous membranes, as well as nasal ulcers and perforations. When a solution of chromate contacts the skin, it can produce penetrating lesions known as chrome holes or chrome ulcers, particularly in areas where a break in the epidermis is already present. These ulcers are usually painless but may persist for months. Acute hepatitis with jaundice has also been observed in workers chronically exposed to Cr (VI). Lung cancer is the most serious long-term effect. Low-level environmental exposures have not resulted in adverse effects in human populations. Long-term studies in which animals

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Environmental Medicine: Integrating a Missing Element into Medical Education have been exposed to low levels of chromium in food or water have produced no harmful effects. Laboratory Tests A general medical workup for a patient with suspected chronic chromium exposure might include the following: Screening Tests Complete blood count Blood panel Liver function tests (SGOT or AST, SGPT or ALT, and bilirubin) BUN and creatinine Urinalysis Specialized Tests Blood and urine chromium levels ß2-microglobulin If chromium inhalation has occurred, a chest X ray, pulmonary function testing, and a nasal smear for eosinophils should be included. Direct Biologic Indicators ❑ Chromium can be measured in blood and urine; hair or nail analysis has no clinical value. ❑ The correlation between exposure levels and urinary chromium excretion is useful in occupational settings. When obtaining biologic specimens for chromium analysis, care must be taken to avoid sample contamination and chromium loss during collection, transportation, and storage. For example, use of stainless steel utensils to collect tissue samples may raise tissue chromium levels, as will stainless steel grinding and homogenizing equipment. Some plastic containers contain significant amounts of teachable chromium; therefore, specially prepared acid-washed containers should be obtained from the laboratory. Considerable care also must be taken in the analysis to minimize chromium volatilization during sample ashing. Another difficulty in the available techniques is the inability to distinguish between Cr (III) and Cr (VI). This is particularly important in environmental samples since Cr (VI) has been associated with serious health hazards, whereas Cr (III) is of far less concern. Blood or serum chromium levels. Blood distribution of chromium appears to be divided evenly between plasma and erythrocytes. In the absence of known exposure, whole blood chromium concentrations are in the range of 2.0 to 3.0 µg/100 mL; lower levels are seen in rural areas, and higher levels occur in large urban centers. Values above background levels are considered potentially toxic, but levels have not been correlated with specific physiologic effects. Chro-

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Environmental Medicine: Integrating a Missing Element into Medical Education mium rapidly clears from the blood, and measurements relate only to recent exposure. Urinary chromium levels. Wide individual variation in metabolism and rapid depletion of body burden limit the value of urinary chromium monitoring. Urinary chromium excretion reflects absorption over the previous 1 or 2 days only. If sufficient time has elapsed for urinary clearance, a negative biomonitoring result can occur even with injurious past exposure. Assuming no source of excessive exposure, urinary chromium values are typically less than 10 µg for a twenty-four-hour period. In occupational settings, a urinary chromium concentration of 40 to 50 µg/L immediately after a workshift reflects exposure to air levels of 50 µg/m3 of soluble Cr (VI) compounds, a concentration associated with nasal perforations in some studies. The American Conference of Governmental Industrial Hygienists (ACGIH) intends to recommend a workplace biologic exposure index (BEI) for total urinary chromium as follows: no more than 10 µg chromium/g creatinine increase during a work shift, and a urinary value of less than 30 µg chromium/g creatinine at the end of the work week. Chromium levels in hair and nails. Hair or nail analysis is of little use in evaluating an individual patient since it is impossible to distinguish chromium bound within the hair during protein synthesis from chromium deposited on the hair from dust, water, or other external sources. Populations with no known chromium exposure reportedly have hair levels ranging from 50 to 1000 ppm chromium. (6) Analysis of the tap water in the patient’s home reveals a greenish tinge and a chromium concentration of 746 µg/L. Your diagnosis is chromium toxicity. Are there any other tests the patient should undergo? _________________________________________________________________ _________________________________________________________________ (7) The patient described in the case study insists on obtaining a hair analysis. The chromium content of the hair sample is 1038 ppm. How will you interpret this result? _________________________________________________________________ _________________________________________________________________

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Environmental Medicine: Integrating a Missing Element into Medical Education Treatment and Management Acute Exposure ❑ No proven antidote is available for chromium poisoning. ❑ Acute poisonings are often fatal regardless of therapy. Treatment in cases of acute, high-level chromium exposure is usually supportive and symptomatic. Supportive measures may include ventilatory support, cardiovascular support, and monitoring for renal and hepatic function. When renal function is compromised, urine alkalinization and maintenance of adequate urine flow are important. Progression to anuria is associated with poor prognosis. If the eyes and skin are directly exposed, flush with copious amounts of water. Topical ascorbic acid has been successfully used to prevent chromium dermatitis and dermal burns caused by dichromate. Gastric lavage with magnesium hydroxide or another antacid may be useful in cases of chromium ingestion. Fluid and electrolyte balance is critical. The efficacy of activated charcoal has not been proven. Hemodialysis, exchange transfusions, or chelating agents such as BAL (dimercaprol) or EDTA (ethylenediaminetetraacetic acid) have not been shown to be effective in the treatment of human poisoning. Orally administered ascorbic acid was found to be protective in experimental animals and was reported beneficial in at least one patient after chromium ingestion. Chronic Exposure ❑ Treatment consists of removal of the patient from further chromium exposure, reliance on the body’s naturally rapid clearance of the metal, and symptomatic management. In most patients with chronic, low-dose exposure, no specific treatment is needed. The mainstay of management is removing the patient from further exposure and relying on the urinary and fecal clearance of the body burden. Although normal urinary excretion is quite rapid, forced diuresis has been used. Except in the lungs, only small amounts of chromium are retained several weeks after exposure has ceased. Dermatitis and liver and renal injury will not progress after removal from exposure and, in most cases, the patient will recover. Weeping dermatitis can be treated with 1% aluminum acetate wet dressings, and chrome ulcers can be treated with topical ascorbic acid. If the exposure has been lengthy (i.e., 2 to 3 years), the increased risk of lung cancer should be discussed with the patient. Although no reliable tests are currently available to screen patients for lung cancer, the physician can intervene with advice and education in smoking cessation, exposure to other known pulmonary carcinogens, and in general, preventive health education. Annual chest X rays may be advisable in carefully selected cases.

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Environmental Medicine: Integrating a Missing Element into Medical Education (8) What is the recommended treatment for the patient described in the case study? _________________________________________________________________ _________________________________________________________________ _________________________________________________________________ _________________________________________________________________ Standards and Regulations Table 1 summarizes the U.S. standards and regulations for chromium salts, which are discussed in more detail below. The Workplace Air ❑ OSHA mandates an 8-hour time-weighted average of 100 µg/m3 for chromic acid and chromates. In 1985, the Occupational Safety and Health Administration (OSHA) mandated an 8-hour workday, 40-hour workweek permissible exposure limit (PEL) of 100 µg CrO3/m3 for chromic acid and chromates (ceiling). For soluble Cr (VI) salts the PEL is an 8-hour time-weighted average (TWA) of 500 µg Cr/m3. For chromium metal and for insoluble salts the TWA is 1000 µg Cr/m3. NIOSH’s recommended exposure limit is a 10-hour TWA for carcinogenic Cr (VI) compounds of 1 µg Cr (VI)/m3. For noncarcinogenic Cr (VI) compounds (a category which includes chromic acid), the recommended exposure limit is 25 µg Cr (VI)/m3 as a 10-hour TWA and a 15-minute ceiling of 50 µg Cr (VI)/m3. Based on current evidence, NIOSH considers the noncarcinogenic Cr (VI) compounds to be the mono- and dichromates of hydrogen, lithium, sodium, potassium, rubidium, cesium, and ammonia, and chromic acid anhydride. Carcinogenic Cr (VI) compounds comprise any and all Cr (VI) materials not mentioned in the noncarcinogenic group above.

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Environmental Medicine: Integrating a Missing Element into Medical Education Environment Air ❑ No federal emission standard currently exists for chromium. EPA does not have an emission standard for chromium and, therefore, does not regulate chromium levels in ambient air. Drinking Water ❑ The current maximum contaminant level for chromium in drinking water is 50 µg/L. EPA has a current enforceable standard of 50 µg/L (50 ppb) total chromium in drinking water. In May 1989, EPA recommended a maximum contaminant level (MCL) of total chromium in drinking water of 100 µg/L (100 ppb). Action on the proposed standard has received public comment, and action will likely be taken by EPA in December 1990. Table 1. Standards and regulations for chromium Agency* Focus Level Comments ACGIH Air-Workplace 50µg/m3 Advisory; TWA† to avoid carcinogenic risk from certain insoluble chromium compounds NIOSH Air-Workplace 1 µg/m3 Advisory; TWA† (10-hour) for carcinogenic Cr (VI) salts 25 µg/m3 TWA† (10-hour) for noncarcinogenic Cr (VI) salts, including chromic acid 50 µg/m3 15-minute ceiling limit for noncarcinogenic Cr (VI) salts OSHA Air-Workplace 100 µg/m3 Regulation; PEL§ for chromic acid and chromates (ceiling) 500 µg/m3 PEL§ for soluble chromic salts (8-hour TWA†) 1000 µg/m3 PEL for chromium metal and insoluble salts (8-hour TWA†) EPA Air-Environment N/A Under review Drinking-Water 50 µg/L Regulation; current MCL¶ for total chromium; proposed MCL is 100 µg/L *ACGIH=American Conference of Governmental Industrial Hygienists; EPA=Environmental Protection Agency; NIOSH=National Institute for Occupational Safety and Health; OSHA= Occupational Safety and Health Administration †TWA (Time-Weighted Average)=time-weighted average concentration for a normal workday and 40-hour workweek to which nearly all workers may be repeatedly exposed §PEL (Permissible Exposure Limit)=an allowable exposure level in workplace air ¶MCL (Maximum Contaminant Level)=enforceable standard for drinking water

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Environmental Medicine: Integrating a Missing Element into Medical Education Suggested Reading List General Reviews Burrows D, ed. Chromium: metabolism and toxicity. Boca Raton, FI: CRC Press, Inc., 1983. Mertz W. Clinical and public health significance of chromium. In: Clinical, biochemical and nutritional aspects of trace elements. New York: Alan R.Liss Inc., 1982:315–23. Sawyer HJ. Chromium and its compounds. In: Zenz C, ed. Occupational medicine, principles and practical applications. Chicago: Year Book Medical Publishers, Inc., 1988:531–9. Carcinogenicity Davies JM. Lung cancer mortality among workers making lead chromate and zinc chromate pigments at three English factories. Br J Ind Med 1984;41:158–69. Hayes RB. Review of occupational epidemiology of chromium chemicals and respiratory cancer. Sci Total Environ 1988;71:331–9. Levy LS, Martin PA, Venitt S. Correspondence: carcinogenicity of chromium and its salts. Br J Ind Med 1987;44:355–7. Norseth T. The carcinogenicity of chromium. Environ Health Perspect 1981;40:121–30. Norseth T. The carcinogenicity of chromium and its salts. Br J Ind Med 1986;43:649–51. Renal Effects and Urinary Excretion Kirschbaum BB, Sprinkel FM, Oken DE. Proximal tubule brush border alterations during the course of chromate nephropathy. Toxicol Appl Pharmacol 1981;52:19–30. Lindberg E, Vesterberg O. Monitoring exposure to chromic acid in chromeplating by measuring chromium in urine. Scand J Work Environ Health 1983;9:333–40. Lindberg E, Vesterberg O. Urinary excretion of proteins in chromeplaters, exchromeplaters and referents. Scand J Work Environ Health 1983;9:505–10. Powers WJ, Gad SC, Siino KM, Pechman JC. Effects of therapeutic agents on chromium-induced acute nephrotoxicity. In: Serrone DM, ed. Chromium symposium 1986: an update. Pittsburgh, PA: Industrial Health Foundation, Inc., 1986:79–86. Related Government Documents Agency for Toxic Substances and Disease Registry. Toxicological profile for chromium. Atlanta: Department of Health and Human Services, Public Health Service, 1989. NTIS report no. PB/89/236665/AS. Environmental Protection Agency. Health assessment document for chromium. Research Triangle Park, NC: Environmental Protection Agency, Environmental and Criteria Assessment Office, 1984. EPA report no. 600/ 8–83–014F.

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Environmental Medicine: Integrating a Missing Element into Medical Education Environmental Protection Agency. Health effects assessment for hexavalent chromium. Cincinnati, OH: Environmental Protection Agency, Environmental and Criteria Assessment Office, 1984. EPA report no. 540/ 1–86–019. Environmental Protection Agency. Health effects assessment for trivalent chromium. Cincinnati, OH: Environmental Protection Agency, Environmental and Criteria Assessment Office, 1984. EPA report no. 540/1–86– 035. Answers to Pretest and Challenge Questions Pretest The Pretest can be found on page 1. A problem list for this patient would include the following: upper and lower respiratory irritation multiple skin lesions and edema of the hands loss of appetite and weight loss liver and renal dysfunction cigarette smoking Information suggesting an environmental etiology includes the following: onset of the patient’s symptoms coincide with activity outside the usual routine; the patient mentions he first noticed the sores on his hands and forearms while digging up the sewage system to make repairs. Another clue to a possible environmental cause is temporary relief of symptoms when the patient leaves his usual habitus, as occurred when he visited Chicago. Proximity of the patient’s home to an industrial facility (i.e., the electroplating plant) is also an important clue. You may identify possible causes for the dermal lesions by consulting a dermatologist. The cause of the persistent (2 to 3 months) respiratory symptoms that do not respond to OTC decongestants in a person with no history of allergies should be pursued; the patient should be queried about whether the onset of symptoms coincided with the move to his home, whether odors have emanated from the plant, etc. More information regarding the patient’s observations and activities while digging up the sewage system also may be helpful. See answer to Challenge question 8. Challenge Challenge questions begin on page 4. The most important pathways for possible chromium exposure in this case are dermal contact during the unearthing of the sewage system; inhalation of emissions from the plant or soil particles if the pond dries up; and ingestion, if the drinking water has been contaminated by effluents from the plant.

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Environmental Medicine: Integrating a Missing Element into Medical Education Minor sources (inhalation) of chromium may be road and cement dust, erosion products of brake linings and emissions from automotive catalytic converters, and tobacco smoke. Cigarettes contain 0.24 to 14.6 mg/kg chromium, although it is not known how much of this is inhaled. Foodstuffs (ingestion) generally contain extremely low chromium levels. If effluent from the plant has reached the groundwater, community residents who drink well water may be at risk. Airborne plant emissions may have also reached nearby residents. Workers at the plant who prepare the plating baths and work near them may be receiving significant exposure. Chromium (VI) is a powerful oxidizing agent. In the plasma and cells, it is readily reduced to chromium (III), which is excreted in the urine. Yes, persistent dermal ulcers, respiratory tract irritation, and pulmonary sensitization are all possible effects of chromium exposure. While it cannot be ruled out, it is unlikely that the dermal and inhalation chromium exposure of this patient will cause lung cancer. Persons who have developed lung cancer after chromium exposure were workers who had significant inhalation exposure for 2 years or longer. Because this patient’s inhalation exposure is at ambient air levels and probably of 2 years duration at most, any increase in his relative risk would not be great. The patient should be advised to stop smoking cigarettes because smoking may act synergistically to increase risk and is itself a significant risk factor for lung cancer. The data is insufficient to estimate the risk from ingestion of the contaminated drinking water. If exposure was recent, chromium levels in blood or urine may be used to confirm exposure. Renal function should be tested (urinalysis, BUN, creatinine, and ß2-microglobulin) to determine if renal tubular damage has occurred. No useful interpretations can be drawn from the hair analysis. A result of 1038 ppm is beyond the range for unexposed persons (50 to 1000 ppm); however, the sample could have been environmentally contaminated with chromium from the water during bathing, or by chromium in ambient air polluted by the plant emissions. There are no standard methods for obtaining a hair sample nor for washing and preparing it for analysis, and these techniques can greatly influence results. Finally, there is no research that proves a correlation between chromium content of hair and exposure levels or physiologic effects; therefore, the result has no clinical significance. If the sources of chromium exposure can be eliminated for this patient, except for the skin lesions, no further treatment would be required. Topical ascorbic acid has been useful in the treatment of chrome ulcers and 1% aluminum acetate wet dressings can be used to treat the dermatitis. This patient’s case may be a sentinel for community exposure. You should contact the local health department, OSHA, and EPA to report your patient’s adverse effects and discuss your suspicions of the chromium source. Chromium levels in and around the plant should be measured. If a hazard exists, workers should be provided proper protective gear, trained, and medically monitored. Since EPA does not currently have an emission standard, it may be difficult to abate the atmospheric source of chromium. Decontamination of the pond site may require regulatory action and litigation. Residents who use well water should be encouraged to use an alternate water source for drinking and cooking.