Case Study

A 35-year-old carpenter with peripheral neuropathy and skin lesions

A 35-year-old, fair-skinned male is referred to your clinic for evaluation. His symptoms began approximately 3 months ago, with the insidious onset of numbness and tingling in his toes and fingertips, progressing slowly in the ensuing weeks to involve the feet and hands in a symmetric “stocking-glove” fashion. In the past 2 to 3 weeks, the tingling has taken on a progressively painful, burning quality and he has noted weakness in gripping tools. No ataxia, dysphagia, visual symptoms, or bowel or bladder incontinence have been noted, and he has not complained of headaches, back or neck pain, or confusion. Except as noted, the review of systems is otherwise negative.

The patient's medical history is remarkable for a flu-like illness approximately 4 months ago characterized by 3 to 4 days of fever, cough, diarrhea, and myalgias, which resolved spontaneously.

Further questioning reveals the patient has been a carpenter since completing high school 17 years ago. For the last 10 years, he has lived in a rural, wooded area in a home he built. Approximately 10 months ago he was married and moved with his wife, an elementary school teacher, into a newly built home on an adjacent parcel of land. The patient consumes one to two alcoholic drinks a week, and quit smoking 2 years ago after a 15-pack-year history. He takes one multivitamin a day but no prescription medications. Family history is unremarkable; his wife, parents, and two younger brothers are in good health.

Neurologic examination reveals diminished proprioception in the hands and feet, with a hyperesthetic response to pinprick sensation on the soles. Motor bulk and tone are normal, but there is slight bilateral muscular weakness in dorsiflexors of the toes and ankles, wrist extensors, and hand intrinsics. Reflexes are absent at the ankles and 1+ at the biceps and knees. Coordination and cranial nerve function are within normal limits. Dermatologic examination reveals brown patches of hyperpigmentation, with scattered overlying pale spots in and around the axillae, groin, nipples, and neck. The palms and soles show multiple hyperkeratotic corn-like elevations 4 to 10 mm in diameter. Three irregularly shaped, sharply demarcated, erythematous, scaly plaques, measuring 2 to 3 cm, are noted on the patient's torso. The remainder of the physical examination is normal.

On initial laboratory evaluation, the CBC shows slight macrocytic anemia with hematocrit 35% (normal range 40% to 52%), and MCV 111 fL (normal range 80 to 100 fL). White blood cell count is 4.3×10³/mm³ (normal range 3.9 to 11.7×10³/mm³); the differential reveals moderate elevation of eosinophils at 9% (normal range 0% to 4%). Occasional basophilic stippling is noted on the peripheral smear. Liver transaminases are slightly elevated. BUN, creatinine, and urinalysis are normal.

(a) What problem list is suggested for this patient?

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(b) What further investigations would you undertake at this time?

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(c) What treatment options would you consider?

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Answers to Pretest questions can be found in Challenge answers (2) through (10) on pages 23–24.

Exposure Pathways

❑ Environmental sources of arsenic exposure are food, water, and air.

❑ The relative toxicity of an arsenical depends primarily on its chemical type, valence state, solubility, and physical form.

❑ Except in the semiconductor industry, commercial use of arsenic has been declining since the 1960s.

Arsenic is ubiquitous in the environment. It is released into the air by volcanoes, through weathering of arsenic-containing minerals and ores, and by commercial or industrial processes. In industry, arsenic is a byproduct of the smelting process for many metal ores such as lead, gold, zinc, cobalt, and nickel. Other potential sources of arsenic exposure are the following:

Natural Sources

Arsenic-containing mineral ores

Groundwater (especially near geothermal activity)

Commercial Products

Wood preservatives

Pesticides

Herbicides (weed killers, defoliants)

Fungicides

Cotton desiccants

Cattle and sheep dips

Paints and pigments

Anti-fouling paints

Leaded gasoline

Fire salts (multicolored flame)

Food

Wine (grapes sprayed with arsenic-containing pesticides)

Tobacco (plants sprayed with arsenic-containing pesticides)

Seafood (especially bivalves, certain cold water and bottom-feeding finfish, seaweed)

Industrial Processes

Purifying industrial gases (removal of sulfur)

Burning fossil fuels

Burning wood treated with arsenic preservatives

Electronics manufacturing (microwave devices, lasers, light-emitting diodes, photoelectric cells, semiconductor devices)

Hardening metal alloys

Preserving animal hides

Bronze plating

Clarifying glass and ceramics

Medicinals

Fowler's solution

Antiparasitic drugs (carbasone)

Donovan's solution

Folk remedies (“Asiatic pill,” kushtay, yellow root)

Kelp-containing health foods

Some naturopathic remedies

Arsenic exists in three common valence states: the metalloid (0 oxidation state), arsenite (trivalent state), and arsenate (pentavalent state). Arsenic-containing compounds vary in their toxicity to mammals, depending on valence state, whether it is in the inorganic or organic form, physical state—gas, solution, or powder—and factors such as solubility, particle size, rates of absorption and elimination, and presence of impurities. With few exceptions, inorganic arsenic is more toxic than organic arsenic. The toxicity of trivalent arsenite is typically greater than that of pentavalent arsenate, but little is known about the toxicity of zero valent arsenic. Arsine gas (AsH₃), used mainly in the microelectronics industry, produces a clinical syndrome very different from other arsenic compounds and is the most toxic arsenical.

Until the 1940s, arsenicals (Salvarsan and Fowler's solution) were widely used in the treatment of various diseases such as syphilis and psoriasis. Arsenicals are still used as antiparasitic agents in veterinary medicine, and, in some countries, they are occasionally used to treat trypanosomiasis and amebiasis in humans. Arsenic is also found in some homeopathic and naturopathic preparations, and in folk remedies such as kushtay, a tonic used in Asian cultures to cure various sexual disorders.

Commercial use of arsenic peaked in the 1960s and since then has steadily declined. As of 1987, 74% of the arsenic used in the United States is for wood preservation, as compared to less than 1% for semiconductor manufacture. However, commercial use of arsenic in the microelectronics industry is increasing rather than declining. Gallium arsenide (GaAs) is used in integral components of discrete microwave devices, lasers, light-emitting diodes, photoelectric chemical cells, and semiconductor devices. The use of arsine gas (AsH₃) as a dopant in the production of semiconductors is also expected to increase, although substitutes of lower toxicity such as tributylarsine have recently been used. A source of arsine exposure is accidental release while manufacturing, transporting, or using the gas. More often, however, arsine forms unexpectedly when acid or other reducing substances are added to arsenic-containing compounds, such as metals in which arsenic is a low-level contaminant.

In the general population, the main route of arsenic exposure is via ingestion of arsenic-containing food and water. It has been estimated that the average daily dietary intake of arsenic by adults in the United States is 50 micrograms (µg) per day (range of 8 to 104 µg), of which about 18 µg is inorganic arsenic. Meat, fish, and poultry account for 80% of dietary arsenic intake. Fish, seafood, and algae also contain high concentrations of arsenic in the form of arsenobetaine and arsenocholine, sometimes referred to as “fish arsenic.” Fish arsenic has low toxicity to humans and is rapidly excreted in urine. Wine made from grapes sprayed with arsenic-containing pesticides may have appreciable levels of arsenic. Smokers may also inhale small amounts of arsenic as a result of pesticide residue on tobacco leaves.

Well water contaminated by natural sources such as arsenic-containing bedrock has been reported to be the cause of arsenic toxicity throughout the world, including areas of the United States, Germany, Argentina, Chile, Taiwan, and the United Kingdom. The areas in the United States with the highest natural groundwater concentrations of arsenic are the Southwest, Northwest, Alaska, and other areas near geothermal activity. Groundwater may also contain elevated concentrations of arsenic due to contamination from arsenical pesticide runoff. A study conducted in 1970 reported that up to 1% of community water supplies in the United States had arsenic concentrations exceeding 10 ppb. (The U.S. Environmental Protection Agency's [EPA] proposed maximum contaminant level for arsenic in drinking water is 50 parts per billion [ppb].) Both the trivalent and pentavalent forms of inorganic arsenic can be found in drinking water.

Who's At Risk

❑ Workers in Industries producing or using arsenic-containing compounds are potentially at risk.

❑ Persons whose water supply contains high levels of arsenic or those living near sources of high ambient air levels of arsenic are at increased likelihood of exposure.

The quantity of arsenic released by human activities exceeds amounts released from natural sources at least threefold. The major sources of arsenic release to the environment are smelters and pesticides. Besides refinery workers and farmers, other workers at increased risk of arsenic exposure include those in the industries listed on page 2. People living near smelters and other arsenic-emitting facilities also have potential risk of exposure from fugitive airborne emissions and groundwater contamination.

❑ Arsenic can cross the placenta, increasing the likelihood of exposure to the fetus.

Arsenic is notorious as a poison because white arsenic (arsenic trioxide) has no odor or taste and is available in inexpensive products such as pesticides. Most arsenic poisonings are due to unintentional ingestion by children. In 1989, EPA instituted a phaseout of certain arsenic-containing ant poisons in an effort to reduce the incidence of children's arsenic ingestion.

Burning plywood treated with an arsenate wood preservative in a poorly ventilated cabin has been blamed for poisoning a family in rural Wisconsin. Green wood or pressed wood treated with copper arsenate to prevent mildew is commonly used in marine applications, patio decks, and recreational structures for children's playgrounds. Cutting this wood or erosion of the veneer may lead to arsenic exposure. Children who play on wood structures treated with copper arsenate have increased likelihood of dermal contact or ingestion of the arsenical through normal mouthing and play activities.

Methyl transferase enzymes play a necessary role in the methylation of arsenic in mammals. The effect of dietary deficiencies and genetic variability on methylating capacity may have important implications for tissue distribution and individual susceptibility to arsenic toxicity. Experimental animals fed protein-deficient diets while exposed to high levels of arsenic have shown a decreased methylating capacity, which has led to increased deposits of arsenic in liver, lung, and other organ sites, and presumably increased susceptibility to arsenic toxicity.

Arsenic can cross the placenta, exposing the fetus. Significant levels of arsenic were found in an infant born 4 days after the mother ingested arsenic in a suicide attempt. Increased incidence of spontaneous abortions, infant congenital malformations, and decreased birth weights have been reported among women and their offspring living near a smelter in Sweden; however, it is not clear that these events can be ascribed to arsenic alone.

Biologic Fate

❑ The primary routes of arsenic entry into the human body are ingestion and inhalation; percutaneous absorption has been reported in occupational settings.

❑ Most tissues rapidly clear arsenic except for skin, hair, and nails.

In humans, soluble forms of ingested arsenic are well absorbed from the gastrointestinal tract (60% to 90%). The amount of arsenic absorbed by inhalation has not been determined precisely, but is thought to be in this range. Dermal absorption is generally negligible, although toxic systemic effects have resulted from rare occupational accidents where either arsenic trichloride or arsenic acid was splashed on workers' skin. Airborne arsenic in the workplace is generally in the form of arsenic trioxide. Its particle size determines whether arsenic will reach the lower respiratory tract or be deposited in the upper airways and be swallowed after mucociliary clearance. Autopsies performed on retired smelter workers show that arsenic-containing particles may remain in the lungs for years.

❑ Arsenic undergoes biomethylation to less toxic metabolites in the liver.

❑ Arsenic is excreted in the urine; most of a single, low-level dose is excreted within a few days after ingestion.

After absorption through the lungs or gastrointestinal tract, arsenic initially accumulates in the liver, spleen, kidney, lungs, and gastrointestinal tract. Clearance from these tissues, however, is rapid. Two to 4 weeks after exposure ceases, most of the arsenic remaining in the body is found in keratin-rich tissues such as skin, hair, and nails, and to a lesser extent, in bones and teeth.

Oxidation-reduction reactions result in some interconversion of arsenate (+5) and arsenite (+3) in vivo. A portion of the arsenite is then biomethylated, predominantly in the liver, to methylarsonic acid and dimethylarsinic acid. The methylation process may represent detoxification because the metabolites exert less acute toxicity in experimental lethality studies.

Methylation efficiency in humans decreases with increasing arsenic dose. When the methylating capacity of the liver is exceeded, exposure to excess levels of inorganic arsenic results in increased retention of arsenic in soft tissues. Cell culture studies suggest that the methylating process is inducible since pretreatment with small amounts of arsenic over a prolonged period increases the methylating efficiency when a large dose is subsequently applied. Fish arsenic is apparently not biotransformed in vivo, but is rapidly excreted unchanged in the urine.

Arsenic is excreted primarily through the kidneys. After low-level exposure to inorganic arsenic, most of the urinary arsenic is present as methylated metabolites. Other less important routes of elimination of inorganic arsenic include sweat, skin desquamation, and incorporation into hair and nails.

After a single intravenous injection of radiolabeled trivalent inorganic arsenic in human volunteers, most of the arsenic cleared through urinary excretion within 2 days, although a small amount of arsenic was found in the urine up to 2 weeks later. The biologic half-life of ingested fish arsenic in humans is estimated to be less than 20 hours, with total clearance in approximately 48 hours. Because arsenic is rapidly cleared from the blood, blood levels may be normal even when urine levels remain markedly elevated.

Physiologic Effects

❑ Because it targets ubiquitous enzyme reactions, arsenic affects nearly all organ systems.

❑ Unlike other arsenicals, arsine gas causes a hemolytic syndrome.

❑ Arsenic is strongly associated with lung and skin cancers and may cause other cancers.

Two mechanisms of arsenic toxicity that may lead to injury in a number of organ systems have been described. It is believed that arsenic's overt toxicity results primarily from its inhibition of critical sulfhydryl-containing enzymes; trivalent arsenite is particularly potent in this regard. Pentavalent arsenate, however, can competitively substitute for phosphate in many biochemical reactions. Replacing the stable phosphate anion with the less stable arsenate anion leads to rapid hydrolysis of the high-energy bonds in compounds such as ATP. Loss of these bonds results in the loss of energy needed for critical steps in cellular metabolism.

Arsine gas poisoning results in a considerably different syndrome from that caused by other forms of arsenic. After inhalation, arsine rapidly fixes to red cells, producing irreversible cell membrane damage. At low levels arsine is a potent hemolysin, causing dose-dependent intravascular hemolysis. At high levels arsine produces direct multisystem cytotoxicity.

Clinical Evaluation

Treatment and Management

Standards and Regulations

Workplace

Air

❑ There is little agreement between governmental regulations and the recommendations of advisory organizations on the acceptable levels of arsenic in the workplace.

The Occupational Safety and Health Administration (OSHA) mandates permissible limits for occupational exposures. The permissible exposure limit (PEL) for arsenic can be no greater than 10 micrograms of inorganic arsenic per cubic meter of air (10 µg/m³), averaged over any 8-hour period for a 40-hour work-week. The recommended exposure limit (REL) set by the National Institute for Occupational Safety and Health (NIOSH), is 2 µg/m³ for a 15-minute ceiling, based on classification of arsenic as a potential human carcinogen (Table 1).

Table 1.

Standards and regulations for inorganic arsenic.

Suggested Reading List

Answers to Pretest and Challenge Questions

(1)

The patient's drinking water, obtained from an artesian well, may contain elevated levels of arsenic due to leaching from natural mineral deposits in the surrounding bedrock. This phenomenon has been noted sporadically throughout the United States, including the Northwest. The patient's employment in carpentry and home construction may place him in contact with arsenic-containing wood preservatives used to treat lumber. Exposure may potentially occur percutaneously in the course of repeatedly handling moist, freshly treated lumber or via inhalation or ingestion of wood dust liberated during sawing. Ingestion or inhalation of ash or flue gas created during burning of arsenic-treated wood in his home fireplace or wood stove may also be a source of household arsenic exposure.

(2)

A sample of the patient's well water can be sent for arsenic analysis. Lists of qualified laboratories may be obtained from the county or state health department. The patient should be questioned about his use of arsenic-treated wood and wood preservatives: arsenic content may be listed on product containers or on Material Safety Data Sheets available from the supplier. The supplier should also indicate whether purchased lumber has been treated with arsenical wood preservatives. The patient should be questioned regarding possible use of arsenic-containing pesticides. In any case of suspected arsenic intoxication, the physician should consider the possibility of intentional poisoning and notify social agencies, if appropriate.

(3)

Because nontoxic trimethylated organic arsenic (arsenobetaine or arsenocholine) ingested in a seafood meal may markedly elevate total arsenic levels, the patient should be questioned about ingestion of seafood within the past 2 days. If seafood has been ingested, laboratory speciation of the urinary arsenic can eliminate the contribution of arsenobetaine or arsenocholine. However, given the patient's clinical presentation, exposure to toxic inorganic arsenic is likely.

In this case, speciation reveals inorganic arsenic present at 1700 µg/L, monomethyl arsonic acid at 2200 µg/L, and dimethyl arsenic acid at 2100 µg/L, confirming that the patient has sustained inorganic arsenic exposure. Since most laboratories do not provide speciation, an alternative approach to interpreting a high urinary arsenic concentration (>500 to 1000 µg/L) if seafood ingestion is a possible factor would be to repeat the measurement with a new urine sample 48 to 96 hours after complete avoidance of seafood. The trimethylated fish arsenic should be completely cleared by that time, but the metabolites of inorganic arsenic, which have slower clearance, should still be present at elevated levels.

(4)

The patient's problem list includes peripheral neuropathy, hyperpigmentation and hyperkeratotic skin lesions, macrocytic anemia, and liver transaminase elevation. The neurologic, dermatologic, and hematologic abnormalities are highly suggestive of chronic arsenic intoxication. He has a characteristic stocking-glove peripheral neuropathy, with predominantly painful sensory symptoms, in the absence of apparent cranial nerve or central nervous system dysfunction. His skin displays hyperpigmentation and palmar-plantar hyperkeratoses characteristic of chronic arsenic ingestion. Consistent laboratory findings include a CBC and peripheral blood smear displaying macrocytic anemia, relative eosinophilia, and occasional basophilic stippling, and a chemistry panel revealing slight elevation in liver transaminases.

(5)

Guillain-Barré syndrome is a primarily motor neuropathy that may begin shortly after a viral infection or immunization. Although the patient's neurological complaints began 1 month after a flu-like illness, examination failed to reveal the characteristic rapid tempo and motor predominance of Guillain-Barré syndrome. Chronic alcoholism may be associated with sensorimotor peripheral neuropathy, macrocytic anemia, and liver transaminase elevation, but cerebellar ataxia and other findings such as hepatomegaly and telangiectasia are usually also present with alcoholism. Thallium intoxication may also result in a sensorimotor peripheral neuropathy. Other diagnostic considerations include paraneo-plastic syndromes, particularly those associated with lung cancer, diabetes mellitus, and certain chronic inflammatory neuropathies.

(6)

The patient's urine should be screened for the presence of arsenic and thallium using either a 24-hour urine collection or a first void morning specimen. A chest X ray should be examined for occult malignancy. Referral for electromyography and nerve conduction studies may be useful to further characterize the peripheral neuropathy and to establish an objective baseline for follow-up measurement. Dermatologic assessment of the patient's skin lesions, possibly including skin biopsy, is indicated to evaluate for cancer or to characterize a precancerous state. The possibility of diabetes mellitus can be investigated by measuring a fasting blood glucose.

(7)

Arsenic-induced skin changes generally result from chronic arsenic exposure and have a latency of several years. Hyperpigmentation typically precedes hyperkeratoses, which in turn precede dermal neoplasms. The presence of both hyperpigmentation and palmar-plantar keratoses in the patient suggests that his arsenic exposure began at least 3 years ago, before consumption of drinking water from his current well. Since he resided on nearby property for 10 years, the well at that location should also be suspected of containing high levels of arsenic.

(8)

The patient's wife, who resides with the patient and may consume the same well water, is at risk for chronic arsenic poisoning. Residents in the surrounding geographical area, who may also be obtaining water from artesian wells should be considered at risk. Former area residents who consumed arsenic chronically before moving away constitute a third group potentially at risk for delayed development of arsenic-associated disease.

(9)

A careful history reveals that the wife, unlike the patient, consumed the well water infrequently, preferring instead to drink bottled soft drinks and juices. Before moving with her husband 10 months ago, she resided in a metropolitan area geographically remote from the present site, where the water was not obtained from wells. Thus, because her arsenic ingestion was markedly lower and of shorter duration than her husband's, she has not yet developed signs or symptoms of chronic arsenic intoxication.

Both the patient and his wife use the arsenic-containing well water for showers and baths. The substantial amount of arsenic in the wife's hair likely reflects external contamination from this source. The arsenic content of the husband's hair is elevated from a combination of external contamination and internal incorporation into the growing hair. The relative contribution from endogenous and exogenous sources cannot be distinguished through bulk hair analysis.

(10)

Immediate cessation of consumption of arsenic-containing well water is the essential first step. Because the utility of chelating agents in reversing or improving the patient's arsenic-related peripheral neuropathy, anemia, and palmar-plantar keratoses is unestablished, chelation treatment cannot be routinely recommended. Analgesics and/or certain tricyclic antidepressants have been reported to be beneficial for the painful dysesthesias associated with peripheral neuropathies. Because some reports indicate that vitamin A analogs (retinoids) may be valuable in the treatment of precancerous arsenical keratoses, referral to a dermatologist for consideration of this treatment is indicated. The patient will remain at risk for the delayed appearance of arsenic-related skin cancer and merits regular, long-term dermatologic follow-up.

(11)

Because of the likelihood that other wells in the area contain elevated levels of arsenic, public health intervention may be necessary to prevent other cases of hazardous arsenic exposure.

Sources of Information

More information on the adverse effects of arsenic and the treatment and managment of arsenic-exposed persons can be obtained from ATSDR, your state and local health departments, poison control centers, and university medical centers. Case Studies in Environmental Medicine: Arsenic Toxicity is one of a series. To obtain other publications in this series, please use the order form on the inside back cover. For clinical inquiries, contact ATSDR, Division of Health Education, Office of the Director, at (404) 639–6204.

Reprinted from the Journal of the American Medical Association

May 11, 1984, Volume 251

Copyright 1984, American Medical Association

Brief Reports

History

A rural family living in northern Wisconsin included the parents, two boys, and four girls ranging from 1 to 30 years old. For three years the parents and children experienced various health problems including sensory hyperesthesias, muscle cramps, recurrent pruritic conjunctivitis, earaches and otitis media, sinusitis, bronchitis, and pneumonitis. A 4-week-old premature neonate was diagnosed as having viral pneumonia and because of recurring respiratory exacerbations was treated with a permanent tracheotomy. The children displayed recurrent “measleslike” rashes consisting of pinpoint hyperemic pruritic dermatitis. The children, who went barefoot, experienced reddened thickened skin on the soles of the feet, and in babies, who crawled on the floor, a rash on the legs, diaper and stomach area, hands, arms, and face developed, which later became desquamated. The youngest member of the family experienced a thrombosed penile artery. All family members complained of malaise, easy fatigue, and a “loose feeling” (lack of sensation) in the arms, hands, feet, and legs. Muscle cramps occurred during the evening hours, often causing the children to awaken the parents from sleep.

By the spring of 1982, headaches were frequent, and the parents complained of “blacking out” for periods of up to two hours followed by feelings of disorientation. The two youngest children had multiple seizures described as grand mal from birth to 1 year. All members experienced frequent nosebleeds and easy bruising. One child was diagnosed by a local physician as having idiopathic thrombocytopenic purpura. The mother's fifth pregnancy resulted in a premature birth diagnosed as placenta previa or abruptio placenta. Most striking was recurring seasonal alopecia, ranging from thinning of hair in the parents to complete baldness in the youngest children. The alopecia was most prominent during the months of March and April, and there was considerable hair regrowth by November and December, after which the cycle would repeat itself (Table 1). All symptoms alleviated during summer months and each year seemed progressively worse in terms of the symptomatology. During the last year the father was unemployed, although he had previously worked in construction and bridge repair. The mother worked as a waitress.

Table 1.

Summary of Family Health Condition During the Last Three Years.

Concerned that the house was the source of the family's health problems, an environmental health group had analyzed blood and urine specimens of family members for carbon monoxide, nitrates, nitrites, thallium, arsenic, calcium, copper, iron, lead, mercury, and zinc, but all results were reported normal. Air analysis of the home by the State Board of Health for carbon monoxide and formaldehyde was within acceptable limits. Concern that the fish in the area might contain heavy metals caused by acid rain, the family had stopped eating fish. Well-water analysis by the State Department of Hygiene was normal for heavy metals, organic compounds, nitrates, nitrites, and radioactivity.

Physical Examination of the Family

The father was admitted to University Hospital, Madison, in June 1982. Somewhat anxious, he admitted to drinking more beer than he should. Physical and neurological examination findings were normal except for congenital clubbing of the fingers and toes. Nerve conduction studies and electromyography (EMG) were normal. Urine zinc excretion of 2.4 mg/L was slightly elevated, with normal levels of copper, lead, and arsenic excretion. Urine thallium levels, done elsewhere, had been reported as normal and were not repeated. Because the alopecia could not be attributed to thallium intoxication, hair samples were analyzed for arsenic, which can also produce hair loss.¹ The hair was found to contain 87 ppm (normal, 0.65 ppm).² Arsenic levels were determined by atomic-absorption spectroscopy after acid digestion.³

Urine, fingernail, and multiple hair samples were collected from the mother and children and analyzed for arsenic. Although no arsenic was detected in the urine, extremely high concentrations were found in the fingernails. Some of the hair arsenic levels were also elevated. Ranges are reported in Table 2. The administration of penicillamine (250 mg three times daily for one week) to the father and one child failed to produce notable urinary arsenic excretion. Clinically, we were unable to detect Mees' lines⁴ (characteristic of acute extreme arsenic exposure) in the fingernails or toenails of the parents or children. Minimal hyperkeratosis was noted on the palm's surface of the three youngest children. Despite subjective complaints of numbness and tingling, no sensory shading or other sensory abnormality was evident on neurological examination. Family pictures confirmed the history of severe alopecia in the children. The hair loss, although less severe, was still present during the summer.

Table 2.

Analysis of Hair and Fingernails Taken From Family Members at Initial Visit at Clinic for Arsenic Determination.

Home Visit

Foul play was initially suspected, but because both parents were clinically involved, the likelihood of intentional poisoning was lessened.

The family lived in a three-bedroom ranch-style house that had been enlarged room by room from a small cabin as the family grew. Multiple food samples, paint, broiler grease, dust from wall heaters, and ash from a wood-burning kitchen stove (the principal source of heat) were collected and analyzed for arsenic. In addition, air samples were taken to be analyzed for arsenic. The food samples contained insignificant quantities of arsenic. The air sample contained 0.300 µg of arsenic per cubic meter of air and 0.040 µg of arsenic per cubic meter of air for the background sample. The ashes from the stove and chimney area contained arsenic in excess of 1,000 ppm. Specimens of dust and ash collected from around the stove area contained arsenic at 100 to 600 ppm.

The high arsenic content in the ash from the stove covering parts of the floor suggested this as a probable source of poisoning. After the analyses were complete, the father reported that for four years he had been burning large amounts of plywood remnants in the kitchen stove. These wood scraps were made available to him from a construction site where he had worked. Much of the plywood had been CCA treated with a solution of 47% chromium oxide, 19% copper oxide, and 34% arsenic pentoxide. The CCA solution was factory applied at a rate of 4.0 to 6.4 kg/cu m of wood.⁵ The proportions of these metals in the ash were the same as in the treatment solution (2.2:1:1.8).⁵ The small wood stove located in the kitchen-dining area was loaded from the top. Adding plywood and wood scraps would allow the escape of ashes and volatilized fumes from the stove. The father would at times remove the stovepipe from the chimney during the winter and carry it through the dining room and hallway outdoors where the flue ash was removed. Usually the stove continued to burn while this maneuver took place. Soot and ashes were prominent in the kitchen, especially on the floor. Because this was the warmest room in the house, the smallest children played in it and the mother also spent most of her time there.

Since June of 1982 when the diagnosis of arsenic poisoning was made, the family has stopped burning the CCA-treated wood, and cleanup operations were made of the home along with attempts to resettle the family in a noncontaminated environment. Because of lack of funds, the family has been unable to relocate, and current efforts are directed at additional cleaning of the house itself, in which the walls and even the soil around the cabin showed arsenic content. The fourth youngster who had a tracheostomy and slept under oxygen at night has had the tracheostomy closed. The dermatologic, respiratory, neurological, and other problems have lessened considerably. Close monitoring of this family's health problems will continue.

Comment

An eight-member family from northern Wisconsin experienced health problems involving the eyes, respiratory system, CNS, gastrointestinal (GI) tract, blood, reproductive system, skin, and hair. The exposure to arsenic, copper, and chromium occurred through ingestion, inhalation, and direct contact. This resulted in chronic exposure (1) to the skin and eyes where it caused a pruritic dermatitis; (2) to the respiratory system where it caused severe irritation and some pneumonic problems (almost fatal to the fourth child); (3) to the GI tract where it caused severe diarrhea; (4) to the CNS where it caused loss of sensation, seizures, blackouts, and headaches; and the most puzzling lesions of all, (5) the seasonal hair loss among all the family members. The youngest members of the family experienced the greatest health problems probably because they were crawling on the floor where the ash had accumulated. The reddened soles of the feet and thickened skin of the palms can be explained by exposure to arsenic⁶ in the ash. It is interesting to note that the two youngest children experienced seizures primarily between the ages of 4 months to 1 year, when they were constantly crawling in the kitchen-dining area. Note that the fingernails contained up to 5,066 ppm of arsenic (Table 2). Unfortunately, detailed EEG studies were not possible.

The exact amount of arsenic, chromium, and copper to which each family member was exposed could not be determined. Only in acute poisoning can arsenic be detected in both blood and urine. Because no arsenic was detected in the urine of family members even after the administration of penicillamine to two members during the summer, we conclude that their exposure was not recent and hope that the body burden is not excessive. Arsenic reacts with protein sulfhydryl groups and any excess leaves the body. Hair and fingernails are the accepted choice for the determination of chronic arsenic exposure.^1,7–12 Levels detected in the hair of the family members indicated the exposure to, but not the exact dose of, arsenic. Mees' lines were not clinically evident when the father was first studied in June 1982. This was because the exposure was chronic and uniform, and not acute and intermittent, or less likely, because Mees' lines had grown out and were clipped off before we saw the family. Also, the penta form of arsenic is less likely to produce Mees' lines and also does not produce the melanotic darkening of the skin or the hyperkeratosis that is commonly produced by the more toxic or lethal trioxide form of arsenic.

The signs and symptoms of chronic low-level exposure to inorganic arsenic in humans have been described,^1,8,13 and arsenic oxide or pentavalent arsenic induces symptoms and signs similar to those experienced by this family.^1,7,13–15 In the commercial process of making outdoor wood and marine plywood, arsenic pentoxide (combined with chromium and copper solution) was used to treat the wood scraps burned by this family. The temperature of wood burning (far less than in smelting) did not change the form of arsenic V oxide, because arsenic was present in the ash as arsenate. Ginsburg¹⁴ in 1965 reported that arsenic V was absorbed by the proximal renal tubules and excreted in the trioxide form in dogs.¹⁴ However, arsenic trioxide, a potentially more toxic form of arsenic, was not detected in our environmental or biologic samples.¹⁵

Since in winter the father took the chimney off the still smouldering stove for brief periods several times a month to clean the stack of creosote, carbon monoxide inhalation may also have added to the toxic hazard. We did not see the family during winter, so unfortunately no carbon monoxide air levels could be measured, and the father only removed the chimney when windows and doors to the kitchen were wide open.

The combined effect of arsenic V, chromium, and copper exposure in the human is unknown and needs further study. We were unable to show changes in EMG and nerve conduction studies (on the father). It is possible that the more lethal trioxide form of arsenic would have produced more severe damage to the peripheral nerves. The children, because of the normalcy of their neurological examination results and other practical constraints, were not available for EMG and nerve conduction studies.

The father experienced severe sinusitis of the maxillary sinus and had recent surgery to reopen fused bones in this area. Nasal septum ulcerations have been reported in cases of long industrial elemental arsenic exposures.¹⁷ The youngest members of this family demonstrated thickened, reddened, peeling soles. Similar lesions have been described in Taiwanese people living where soil and water were high in arsenic and toxic fluorescent alkaloids.⁶ A high incidence of skin cancer was also reported.⁶ Although arsenic has been associated with carcinogenesis in humans,¹⁶ no suggestive changes have been detected in this family.

In the past, inorganic arsenicals were used in agriculture as insecticides, soil sterilants, and herbicides.¹⁷ Monitoring by the Food and Drug Administration has indicated that the level of arsenic in US food supplies is low.¹⁸ Most arsenic is found in the meat-fish-poultry diet, with seafood containing the highest levels. Sources of environmental arsenic include smelters, electric power plants using arsenic-rich coal, and soil and water found in certain parts of the world.¹⁸

Human poisoning from the burning of CCA-impregnated wood has not been previously reported and represents the probable source of arsenic exposure in this family. Fowler¹⁸ warned in 1977 that the burning of CCA-treated wood should be studied as a potential health hazard. Our studies of the kitchen-living area were done in the summer and disclosed notable contamination with CCA-rich ash. In the winter months while the CCA-treated plywood was being burned, we would have anticipated even greater contamination. With the increased popularity of burning wood for household heating purposes, the environmental health hazard of burning CCA-treated wood needs recognition and evaluation. The role of chromium and copper in contributing to these health problems is conjectural. We would suggest that all three elements could be responsible for this kaleidoscopic clinical pattern.

Joy Savides Felker provided advice and secretarial aid and Lee Sjouik, MS, contributed technical assistance.

References

1.

Oettingen WF: Poisoning—A Guide to Clin ical Diagnosis and Treatment , ed 2. Philadelphia, WB Saunders Co, 1958, pp239–242.

2.

Woolson E, Ahronson N: Separation and detection of arsenicals pesticides residues and some of their metabolites by high pressure liquid chromatography-graphite furnace atomic absorption spectro. J Assoc Off Anal Chem 1980; 63:523–528.

3.

Boylen GW, Hardy NL: Distribution of arsenic in nonexposed persons (hair, liver, and urine). Am Ind Hyg Assoc J 1967; 28:148–150. [PubMed: 6029553]

4.

Mees RA: The nails with arsenical polyneuritis. JAMA 1919; 72:1337.

5.

Biologic and economic assessment of pentachlorophenol inorganic arsenicals, and creosote, in Wood Preservatives , Technical Bulletin No. 1658–1, US Dept of Agriculture, 1980, vol 1, pp31–192.

6.

Tseng WP: Effects and dose-response relationships of skin cancer and blackfoot disease with arsenic. Environ Health Perspect 1977; 19:109–119. [PMC free article: PMC1637425] [PubMed: 908285]

7.

Stewart CP, Stolman A: Toxicology—Mech anisms and Analytical Methods. New York, Academic Press Inc, 1960, vol 1, pp202–206.

8.

Moeschlin S: Poisoning—Diagnosis and Treatment New York, Grune & Stratton Inc, 1965, pp162–169.

9.

Creason JP, Hinners TA, Bumgarner SE, et al: Trace elements in hair as related to exposure in metropolitan New York. Clin Chem 1975; 21:603–612. [PubMed: 1116297]

10.

Harrison WW, Yurachek JP, Benson CA: The determination of trace elements in human hair by atomic absorption spectroscopy. Clin Chim Acta 1969; 23:83–91. [PubMed: 5762142]

11.

Harrison WW, Clemena GG: Survey analysis of trace elements in human fingernails by spark source mass spectrometry. Clin Chim Acta 1971; 36:485–492. [PubMed: 5008808]

12.

Harrison WW, Tyree AB: The determination of trace elements in human fingernails by atomic absorption spectroscopy. Clin Chim Acta 1971; 31:63–73. [PubMed: 5101392]

13.

Casarett LJ, Doull J: The Basic Science of Poisons Toxicology. New York, Macmillan Publishing Co Inc, 1975, pp464–465.

14.

Ginsburg JM: Renal mechanism for excretion and transformation of arsenic in the dog. Am J Physiol 1965; 208:832–840. [PubMed: 14286849]

15.

Feldman RG, Niles CA, Kelly-Hayes M, et al: Peripheral neuropathy in arsenic smelter workers. Neurology 1979; 29:939–944. [PubMed: 224345]

16.

International Agency for Research on Cancer (IARC): Arsenic and Arsenic Compounds, IARC monographs on the evaluation of the carcinogenic risk of chemicals to humans. Lyon, France, World Health Organization, IRAC, vol 23, pp39–141.

17.

Woolson EA: Fate of arsenicals in different environmental substrates. Environ Health Perspect 1977; 19:73–81. [PMC free article: PMC1637396] [PubMed: 908316]

18.

Fowler BA: International conference on environmental arsenic: An overview. Environ Health Perspect 1977; 19:239–242. [PMC free article: PMC1637397] [PubMed: 908305]

Case Study

A 10-year-old boy with shortness of breath and recent asbestos exposure

A 10-year-old boy is seen at your office with a chief complaint of shortness of breath. Exertional dyspnea has been present for the previous month and is associated with intermittent dry cough. The patient has no associated fever, chills, or chest pain. Chart review indicates no history of asthma or other pulmonary disease, although the patient has been seen several times for “hay fever.”

The patient is accompanied by his mother, who appears quite anxious. The mother emotionally relates that her 65-year-old cousin has recently been diagnosed with mesothelioma and is dying. Furthermore, he had been a custodian at the patient's school for the previous 3 years, after retiring from his career as a longshoreman. His work at the school involved general cleanup and boiler room maintenance. The mother is afraid that her son's dyspnea and cough are related to asbestos exposure at the school and that he may be developing mesothelioma since he often helped his cousin after school. Recent asbestos removal in the school has increased the mother's concern.

On physical examination, the patient is in no acute distress. Respirations are unlabored. Lung auscultation reveals a diffuse, expiratory wheeze. Spirometry performed in the office shows an FVC of 95% of predicted value and an FEV, of 88% of predicted value with an FEV₁/FVC of 70%. The remainder of the examination is within normal limits. A chest X ray is normal.

(a) Discuss whether the patient's symptoms are related to asbestos exposure.

_________________________________________________________________

_________________________________________________________________

(b) Is the patient at risk for future disease? Explain.

_________________________________________________________________

_________________________________________________________________

(c) Can the cousin's mesothelioma be related to his work as a custodian in the school? Explain.

_________________________________________________________________

_________________________________________________________________

Answers to the Pretest can be found on page 19.

Exposure Pathways

❑ Asbestos exposure occurs primarily through inhalation of fibrous dust.

❑ Insulating materials produced prior to 1975 commonly contain asbestos.

Asbestos is a generic term for a group of six naturally occurring fibrous minerals. The basic unit of asbestos-class minerals is the silicate combined in varying proportions with magnesium, iron, calcium, aluminum, and sodium or trace elements.

There are two major classes of asbestos: serpentine, which contains a magnesium silicate called chrysotile, and amphiboles, which represent a small portion of the world's asbestos consumption and include crocidolite, amosite, anthophyllite, and tremolite. Chrysotile, the sole member of the serpentine group, accounts for 93% of the world's asbestos use.

Asbestos has been used in over 3000 products due to its high tensile strength, relative resistance to acid and temperature, and its varying textures and degrees of flexibility. It does not evaporate, dissolve, burn, or undergo significant reactions with other chemicals, which makes asbestos nonbiodegradable and environmentally cumulative.

Although many applications have been phased out of production, uses of asbestos have included the following:

Commercial

Boilers and heating vessels

Cement pipe

Clutch, brake, transmission components

Conduits for electrical wire

Corrosive chemical containers

Electric motor components

Heat protective pads

Laboratory furniture

Paper products

Pipe covering

Roofing products

Sealants and coatings

Textiles (including curtains)

Homes and Buildings

Duct insulation

Fire protection panels

Fireplace artificial logs or ashes

Furnace insulating pads

Fusebox liners

Heater register tape and insulation

Joint compounds

Patching plaster

Pipe or boiler insulation

Sheet vinyl or floor tiles

Shingles

Textured acoustical ceiling

Underlayment for sheet flooring

Asbestos fibers may result from mining, milling, and weathering of asbestos-bearing rock, and from the manufacture, wear, and disposal of asbestos-containing products. Because of the widespread use of asbestos, its fibers are ubiquitous in the environment.

Although bans and voluntary phaseouts have contributed to declining production of asbestos since the early 1970s, it is still used in construction materials, mostly asbestos cement products. Building insulation materials manufactured since 1975 may no longer contain asbestos; however, products made or stockpiled before the ban remain in many homes.

Indoor air may become contaminated with fibers released from building materials, especially if they are damaged or crumbling. Common sources in homes are sprayed asbestos (“cottage cheese”) ceilings, pipe insulation, boiler coverings, wallboard, and floor and ceiling tiles. Homeowners should not undertake repair or removal of asbestos-containing materials without professional guidance or services.

Although measurable asbestos levels in schools are usually 1000 times below the permissible exposure limit (PEL) for work environments, public concern has led to widespread removal and abatement programs. However, some facilities have higher levels of airborne asbestos after removal than before, indicating that removing asbestos improperly can be more hazardous than leaving it in place.

Street dust may contain fibers from brake linings or crushed asbestos-containing rock used in road construction. Fibrous tremolite, the asbestos commonly found in talc, has also been found in play sand.

Drinking water supplies may become contaminated with asbestos from erosion of natural land sources, discarded mine and mill tailings, asbestos cement pipe, and from disintegration of other asbestos-containing materials transported via rain. Most water supply concentrations are less than 1 million fibers per liter but in some cases have exceeded 100 million fibers per liter. The U.S. Environmental Protection Agency's (EPA) proposed maximum contaminant level for asbestos in drinking water is 7 million fibers (larger than 10 microns in length) per liter.

Who's at Risk

❑ The construction trades have the most heavily asbestos-exposed workers.

❑ Spouses and family members can be exposed through asbestos dust on worker's skin and work clothing.

❑ Cigarette smoke increases the risk of asbestos-associated lung cancer.

In the past, asbestos exposure was associated mainly with mining and milling of the raw material and with workers engaged in product manufacture. Since industrial use has decreased over the last 40 years, these occupational exposures have declined. Today, most exposures occur during repair, renovation, removal, and maintenance of asbestos that was installed years ago. The number of new exposures to the general population from in-place asbestos, however, may be greater in number than the exposures to all earlier workers combined.

The most heavily exposed people in the United States are construction tradespersons. In 1988, there were 6,300,000 active construction workers in the United States. Since most asbestos has been used in construction, and two thirds of today's production is still used in this trade, risk to these workers may be considerable. Carpenters, utility workers, electricians, pipefitters, steel mill workers, sheet metal workers, boilermakers, and laborers are at risk of exposure to asbestos through construction materials, insulation coverings of pipes, boilers, industrial furnaces, and other sources. Mechanics working with brake and transmission products also may be exposed to asbestos.

Secondary exposure occurs when fibers released to the air are inhaled by persons not directly handling asbestos. For example, 4 to 5 million shipyard workers were exposed when a relatively small number of insulation workers applied asbestos to ships' pipes and hulls. Domestic and environmental asbestos exposures may also occur indirectly. Asbestos-related diseases have occurred in family members whose only contact was dust from an exposed worker's clothes. Similar diseases were also found in persons who grew up within one-half mile of an asbestos factory.

Cigarette smoking and exposure to other carcinogens greatly increase the risk of asbestos-associated lung cancer. A comparison of the experiences of 17,800 asbestos insulation workers with matched controls showed that asbestos workers who did not smoke suffered 5 times the number of lung cancer deaths than controls who neither smoked nor worked with asbestos (55 deaths per 100,000 man-years for asbestos workers who did not smoke compared with 11 deaths per 100,000 man-years for controls who were neither asbestos workers nor smokers). Persons who smoked but did not work with asbestos had a death rate of 122 per 100,000 man-years; and among persons with both exposures (asbestos and cigarette smoking), 601 deaths occurred per 100,000 man-years. There is evidence that cigarette smoking in asbestos workers is also associated with increased risk of cancer of the esophagus, oropharynx and buccal cavity, and larynx. Cancers of the stomach, colon-rectum, and kidney, however, do not appear to be synergistically affected by smoking and asbestos exposure since smoking and nonsmoking asbestos workers suffer equal incidences of these health effects. While cancer, when established, may be irreversible, cancer risk is reversible. Data indicate that risk diminishes when smoking ceases.

Biologic Fate

❑ A significant proportion of inhaled asbestos fibers may be retained in the lungs.

❑ The size and shape of asbestos fibers affect the lungs' ability to effectively remove them.

The primary route of asbestos entry into the body is through inhalation. Ingestion of asbestos fibers can occur from drinking contaminated water or after mucociliary clearance from the lungs. The fate of ingested asbestos is still being debated. Asbestos fibers may also lodge in the skin.

Generally, only particles between 0.5 and 5 microns in diameter with a length-to-width ratio of 3:1 will be deposited in the respiratory regions of the lung (alveoli and terminal bronchioles). Larger particles tend to be filtered out in the upper airway and nasopharynx. Smaller fibers tend to remain suspended in the inspired air, and the majority are exhaled. However, asbestos is an exceptional substance: fibers ranging from 5 to 10 microns in diameter can also penetrate to the lower respiratory regions of the lung, where they may have destructive effects.

The fibrous nature of asbestos renders the lungs' defense mechanisms ineffective. Smaller, nonfibrous particles are normally engulfed by macrophages and removed by lymphatic or mucociliary mechanisms. Attempts by the macrophages to engulf fibers can lead to eventual deposition in various tissues of ferrous material in a drumstick configuration called a ferruginous body (asbestos body).

Asbestos fibers can also penetrate to the terminal bronchiolar level and enter the peribronchiolar space, resulting in a fibrogenic response. Because the fibers concentrate in the lower lung fields, there is a tendency for fibrosis to occur first in the lungs' bases, and for pleural effects to be confined to the lower two-thirds of the thorax. Fibrosis results from persistent release of inflammatory mediators such as lysozymes, interleukins, and fibroblast growth factors at the site of asbestos fiber penetration and deposition.

Data do not clearly relate GI tumors or peritoneal mesotheliomas to direct ingestion of asbestos fibers, although persons exposed to asbestos by inhalation have been reported to have a twofold greater risk of colorectal cancer than unexposed persons. Some investigators believe this malignancy is caused by fibers removed from the lungs' upper respiratory regions by ciliary mechanisms and then swallowed. Most reports suggest that ingested asbestos is excreted with the feces. Asbestos bodies have been identified within some human specimens of colorectal adenocarcinomas. Several animal studies have revealed that asbestos fibers are capable of penetrating the GI tract.

Electron microscopy reveals that fibrils result from longitudinal and cross-sectional fragmentation of asbestos fibers. A single asbestos fiber can fracture into hundreds of sub-microscopic fibrils. Research indicates that these uncoated fibrils may be the form that migrates into the peritoneal and pleural spaces.

Physiologic Effects

❑ Asbestos primarily affects the respiratory system. The immune and cardiovascular systems, and possibly the GI system, are also affected by asbestos exposure.

The respiratory, immunologic, cardiovascular, and gastrointestinal systems may be adversely affected by asbestos inhalation and by ingestion subsequent to mucociliary removal from the respiratory tract. Skin nodules from handling asbestos-containing materials may also occur.

Immunologic abnormalities such as increased concentrations of auto-antibodies and depressed lymphocyte responsiveness (page 10) are usually mild or absent in persons who have not developed clinical signs of asbestosis. Cardiovascular effects are secondary to pulmonary changes. Fibrosis in the lung can lead to increased resistance to blood flow through the pulmonary capillary bed, resulting in pulmonary hypertension and compensatory hypertrophy of the right heart.

No deaths due to acute exposure to asbestos have been reported. However, delayed death due to asbestosis and cancer from chronic inhalation exposure has occurred. The risk of developing asbestos-associated disease continues even after exposure has ceased.

Clinical Evaluation

Treatment and Management

❑ Patient education is an important factor in managing asbestos-associated disease.

Management of asbestos-associated diseases begins with patient education regarding smoking cessation and avoidance of pulmonary infections. Awareness of early symptoms of other neoplasms is important, including hoarseness, sores in the mouth, blood in the urine, blood in the stool, and gastrointestinal symptoms. Persons exposed to asbestos should be advised of the increased risk of lung cancer and the synergistic effects of cigarette smoking, although smoking does not affect the development of mesothelioma. Explaining environmentally related cancer risk is difficult because extrapolation of risk from workplace data is impossible in many cases. Maintaining a balance between appropriate concern and avoidance of undue alarm is the goal.

Follow-up of asymptomatic patients exposed to asbestos is recommended to facilitate early diagnosis and intervention. Periodic pulmonary function studies can be helpful in diagnosing early signs of asbestosis.

Standards and Regulations

Suggested Reading List

Answers to Pretest and Challenge Questions

Sources of Information

More information on the adverse effects of asbestos and the treatment and management of asbestos-exposed persons can be obtained from ATSDR, your state and local health departments, and university medical centers. Case Studies in Environmental Medicine: Asbestos Toxicity is one of a series. For other publications in this series, please use the order form on the back cover. For clinical inquiries, contact ATSDR, Division of Health Education, Office of Director, at (404) 639–0730.

Case Study

A 50-year-old diesel mechanic with recurring nosebleeds, fatigue, and weight loss

A 50-year-old man is prompted to visit your office because of a nosebleed that has been recurring for 2 days. He says that this is the third episode of nosebleeds in the last 6 months. He expresses concern that he becomes easily fatigued at work, and 2 months ago he began noticing bruises on his arms and legs, although he does not recall the causes. He has lost more than 12 pounds in the last 2 years, which he attributes to loss of appetite.

History of previous illness includes a fractured arm in childhood. He has had three bad colds in the past 2 years that lasted for more than a week and included coughing and breathing difficulty. The patient occasionally drinks beer; he quit smoking cigarettes 4 years ago. He does not have allergies and is taking no medications at this time.

On examination, you find a muscular man with somewhat pale and dry skin. Conjunctivae are pale. Numerous ecchymoses and petechiae are noted on arms and legs. Many seem to be old with incomplete healing. BP is 138/84; HR is 94. Temperature is normal. His throat is moderately inflamed, and prominent cervical nodes are palpable. Examination is otherwise within normal limits.

On further questioning, you learn that the patient is a diesel mechanic and has worked on trucks for the same employer for the previous 12 years. He and his wife divorced 8 years ago; his wife became nervous and withdrawn after two miscarriages, which led to marital stress. He has lived in his home for the past 16 years. He has a daughter, age 16, who lives with his ex-wife.

Laboratory studies reveal the following: glucose, BUN, and bilirubin within normal limits; Hgb 10.2 g/dL (normal 14.0–18.0); Hct 32.6% (44.8–52.0); RBC 3.32 mil/mm³ (4.3–6.0); MCV 98 fl (80–100); MCH 31 pg (26–31); MCHC 31% (31–36); WBC 1500 mm³ (5000–10,000); segs 60% (40–60); bands 1% (0–5); lymphs 31% (20–40); monos 8% (4–8); platelets 50,000/mm³ (150,000–400,000). A chest X ray is negative except for some suggestion of hyperlucency; EGG is normal.

(a) What is the problem list for this patient? What is the differential diagnosis?

_________________________________________________________________

(b) What additional testing would you recommend?

_________________________________________________________________

(c) What measures would you take to manage the case and treat this patient?

_________________________________________________________________

Answers to the Pretest can be found in Challenge answers (3) through (7) on pages 17 and 18.

Exposure Pathways

❑ Benzene is commonly used as a solvent and as a raw material in chemical syntheses.

❑ Benzene is added to unleaded motor fuels for its antiknock characteristics.

❑ Because benzene plays such a vital role in many industrial processes and is a component of gasoline, it is widespread in the environment.

Benzene (C₆H₆) is the first member of a series of aromatic hydrocarbons recovered from refinery streams during catalytic reformation and other petroleum processes. It is a clear, colorless, highly flammable liquid at room temperature. Its vapor is heavier than air and can travel to a source of ignition and flash back. It has a pleasant odor detectable at concentrations greater than 4 parts per million (ppm). (The workplace permissible exposure level [PEL] is 1 ppm). Common synonyms for benzene include benzol, cyclohexatriene, phenyl hydride, and coal tar naphtha.

Benzene is one of the world's major commodity chemicals. Its primary use (85% of production) is as an intermediate in the production of other chemicals, predominantly styrene (for styrofoam and other plastics), cumene (for various resins), and cyclohexane (for nylon and other synthetic fibers). Benzene is an important raw material for the manufacture of synthetic rubbers, gums, lubricants, dyes, pharmaceuticals, and agricultural chemicals.

Benzene is a natural component of crude and refined petroleum. The mandatory decrease of lead alkyls in gasoline has led to an increase in the aromatic hydrocarbon content of gasoline to maintain high octane levels and antiknock properties. In the United States, gasoline typically contains less than 2% benzene by volume, but in other countries the benzene concentration may be as high as 5%.

Because of its lipophilic nature, benzene is an excellent solvent. Its use in paints, thinners, inks, adhesives, and rubbers, however, is decreasing and now accounts for less than 2% of current benzene production. Benzene was also an important component of many industrial cleaning and degreasing formulations but now is replaced mostly by toluene, chlorinated solvents, or mineral spirits. Although benzene is no longer added in significant quantities to most commercial products, traces of it may still be present as a contaminant.

Because of its many uses, benzene is widespread in the environment. It is a component of both indoor and outdoor air pollution. Benzene levels measured in ambient air have ranged from less than 0.001 ppm in pristine rural areas to more than 0.1 ppm in urban areas. Sources of benzene in air are usually associated with chemical manufacturing or gasoline, including gasoline bulk-loading and discharging facilities and combustion engines (such as in automobiles, lawn mowers, and snow blowers). In almost all cases, benzene levels inside residences or offices are higher than levels outside. Benzene levels are also usually higher in homes with attached garages and those occupied by smokers. In the fall and winter when buildings are less-well ventilated, benzene levels are even higher. The Environmental Protection Agency (EPA) classifies benzene as a Group A^* carcinogen and has estimated that a lifetime exposure to 0.004 ppm benzene in air will result in, at most, 1 additional case of leukemia in 10,000 people exposed. (EPA risk estimates assume there is no threshold for benzene's carcinogenic effects.)

Leakage from underground storage tanks and seepage from landfills or improper disposal of hazardous wastes has resulted in benzene contamination of groundwater used for drinking. Effluent from industries is also a source of ground-water contamination. EPA'S Office of Drinking Water has estimated that lifetime exposure to a benzene concentration of 68 parts per billion (ppb) in drinking water would correspond to, at most, 1 additional cancer case in 10,000 people exposed. (The current EPA maximum contaminant level [MCL] for benzene in drinking water is 5 ppb.) In addition to being ingested, benzene in water can also be absorbed through wet skin and inhaled as it volatilizes during showering or laundering.

Persons who smoke one pack of cigarettes a day inhale a daily dose of approximately 1 milligram of benzene, which is about one-thirtieth of the daily amount inhaled by a worker exposed at the currently permissible workplace level.

Who's at Risk

❑ Two to three million U.S. workers are at risk of benzene exposure.

❑ Alcohol and other drugs that induce the mixed function oxidase (MFO) enzymes may potentiate the effects of benzene.

Workers employed in industries using or producing benzene have the greatest likelihood of exposure. The National Institute for Occupational Safety and Health (NIOSH) estimates that approximately two to three million workers in the United States may be exposed to benzene during refining operations; gasoline storage, shipment, and retail operations; chemical manufacturing; plastics and rubber manufacturing; shoe manufacturing; printing; and activities in chemical laboratories. A review of benzene exposure in the U.S. petroleum industry from 1978 to 1983 indicated that 87% of exposures were below an 8-hour time-weighted average (TWA) of 1 ppm and 98% were below 10 ppm.

In 1980, an estimated 37 million people in this country were exposed to benzene vapors at self-service gasoline stations. During gasoline pumping, atmospheric benzene levels up to 6.6 ppm have been measured, with a 6-hour TWA of 0.1 ppm. This risk has been lowered by installing vapor recapture devices on delivery hoses, which, if used properly, significantly reduce exposure. Catalytic converters have significantly reduced the benzene in automobile emissions.

Benzene is converted to toxic metabolites mostly by mixed-function oxidases (MFO) in the liver and bone marrow. MFO-inducing drugs (e.g., phenobarbital, alcohol) and certain chemicals (e.g., chlordane, parathion) may increase the rate at which toxic metabolites of benzene are formed. Theoretically, persons with rapidly synthesizing marrows—the fetus, infants and children, persons with hemolytic anemia or with agranulocytosis— are at increased risk.

Biologic Fate

❑ Benzene is absorbed well after inhalation or ingestion; in comparison, dermal absorption is slow.

❑ Benzene is metabolized in the liver and bone marrow.

❑ Benzene excretion occurs via the lungs and urine.

Benzene is absorbed rapidly by inhalation and ingestion, and slowly through intact skin. After a 4-hour exposure to approximately 50 ppm benzene in air, human volunteers absorbed about 50% of the amount inhaled.

Distribution of benzene to tissues is dependent on relative perfusion rates. In humans, approximately half of an inhaled dose is distributed to the liver and bone marrow. Benzene accumulation is slow in fat, but the total potential uptake is great because of benzene's high lipid solubility.

Absorbed benzene is metabolized primarily in the liver. Benzene metabolism initially involves oxidation, with phenol as the major metabolite. Further metabolic products formed by the introduction of hydroxyl groups on the aromatic ring include hydroquinone, catechol, and 1,2,4-trihydroxybenzene. These hydroxylated metabolites can be further oxidized to their corresponding quinones or semiquinones. Urinary excretion of small amounts of muconic acid, a straight-chain dicarboxylic acid, indicates that the benzene ring also is opened during metabolism.

Bone marrow is the main target organ of benzene toxicity. It contains the MFO enzymes necessary to metabolize benzene, and although benzene metabolism in bone marrow is not clearly understood, one or more benzene metabolites are suspected as responsible for the hematotoxicity. The metabolites may bind covalently to cellular macromolecules (e.g., proteins, DNA, and RNA), causing disruption of cell growth and replication. The rate of benzene metabolism in bone marrow is lower than that in the liver.

Approximately 50% of absorbed benzene is excreted unchanged via the lungs over a 36-hour period, depending on exercise level and amount of body fat. Respiratory elimination is triphasic, with approximate half-lives of 1 hour, 3 hours, and greater than 15 hours. Urinary excretion of metabolites, primarily phenol, is another important pathway for elimination. Most of the phenol is excreted in the form of sulfate esters and glucuronides. After a single exposure, urinary excretion of phenol and hydroquinone is highest within the first 24 hours and is essentially complete within 48 hours.

Physiologic Effects

❑ Benzene affects primarily the CNS and hematopoietic system.

Benzene exposure affects the central nervous system (CNS) and hematopoietic system and may affect the immune system. Death due to acute benzene exposure has been attributed to asphyxiation, respiratory arrest, CNS depression, or cardiac dysrhythmia. Pathologic findings in fatal cases have included respiratory tract inflammation, lung hemorrhages, kidney congestion, and cerebral edema.

Clinical Evaluation

Treatment and Management

Standards and Regulations

Workplace

Air

❑ The current permissible exposure limit for benzene is 1 ppm.

In 1987, the Occupational Safety and Health Administration (OSHA) instituted a permissible exposure limit for benzene of 1 ppm, measured as an 8-hour time-weighted average (TWA), and a short-term exposure limit of 5 ppm (Table 1). These legal limits were based on studies demonstrating compelling evidence of health risk to workers exposed to benzene. The risk from exposure to 1 ppm for a working lifetime has been estimated to be 5 excess leukemia deaths per 1000 employees exposed. (This estimate assumes no threshold for benzene's carcinogenic effects.) OSHA has also established an action level of 0.5 ppm to encourage even lower exposures in the workplace.

Table 1.

Standards and regulations for benzene.

The National Institute for Occupational Safety and Health (NIOSH) recommends an exposure limit of 0.1 ppm as a 10-hour TWA. NIOSH also recommends that benzene be handled in the workplace as a human carcinogen.

Suggested Reading List

Sources of Information

More information on the adverse effects of benzene and the treatment and management of benzene-exposed persons can be obtained from ATSDR, your state and local health departments, and university medical centers. Case Studies in Environmental Medicine: Benzene Toxicity is one of a series. For other publications in this series, please use the order form on the back of page 21. For clinical inquiries, contact ATSDR, Division of Health Education, Office of the Director, at (404) 639–6204.

In addition to other resources, ATSDR has created a National Exposure Registry for benzene. This registry is one of a series mandated by the Comprehensive Environmental Response, Compensation, and Liability Act of 1980 (CERCLA). ATSDR, in cooperation with the states, will establish and maintain national registries of (1) persons exposed to substances and (2) persons with serious illness or diseases possibly due to exposure. The registries will collect information on the effects of low-level exposures of long duration (i.e., the exposures typically found in populations surrounding hazardous waste sites) and the health outcomes for populations receiving a one-time, high-level environmental exposure (such as those experienced at chemical spill sites). The registries will facilitate the identification and subsequent tracking of persons exposed to a defined substance at selected sites and will coordinate the clinical and research activities involving the registrants. For further information on the benzene registry, please contact ATSDR Division of Health Studies, Office of the Director, at (404) 639–6200.

Answers to Pretest and Challenge Questions

Pretest questions are found on page 1; answers are in (3) through (7) below. Challenge questions begin on page 3.

(1)

Some important are as to explore include amounts and duration of exposure from the following sources:

• – water supply (ingestion)
• – water supply (inhalation or dermal absorption during bathing and laundering)
• – ambient air (fugitive emissions from the chemical plant during its operation and since it was abandoned 9 years ago)
• – occupation (activities, conditions, and time spent as a diesel mechanic)
• – workplace conditions (cleaning of machinery parts, solvents used, protective equipment worn, and the adequacy of ventilation)
• – home environment (use of consumer products that might contain benzene, exposure to personal or passive cigarette smoke)

(For more information, see Case Studies in Environmental Medicine: Taking an Exposure History , ATSDR, October 1992.)

(2)

Theoretically, a person could be at increased risk of benzene's adverse effects if he or she encountered agents or conditions that increased the rate of formation of toxic benzene metabolites through induction of the MFO system. Potential agents include MFO-inducing drugs (e.g., phenobarbital, alcohol); conditions include those causing rapid synthesis of bone marrow. The patient only occasionally drinks beer and did not take medications before his illness, and so he avoids the risk factors of alcohol and medications. However, if the patient is suffering from a hematologic abnormality, as his symptoms and laboratory evaluation suggest, he will have increased risk if benzene exposure continues.

Other persons in the case who may be at increased risk of benzene exposure are those who have had contact with the water supply for a prolonged period of time, although no data exist to quantitate the risk. Included are persons who have lived in the patient's household and members of the community who share the water supply. Community and household members who are at increased risk of benzene's adverse effects theoretically include those with rapidly synthesizing bone marrows and persons with increased MFO-mediated metabolism (e.g., heavy drinkers).

(3)

The patient's problem list includes a clotting disorder, fatigue, ecchymoses and petechiae, and anorexia with concomitant weight loss.

(4)

The hematology study reveals significant thrombocytopenia, leukopenia, and erythropenia. Pancytopenia is caused by the accelerated destruction or decreased production of all cell lines including red blood cells, white blood cells, and platelets. Bone marrow disorders are likely to be the cause, and could result from the following: drug and chemical toxicity (such as benzene toxicity), radiation, infection, nutrient deficiencies (e.g., vitamin B₁₂ and folate), hypersplenism, and marrow replacement syndromes.

(5)

Additional testing for the patient might include coagulation factors, evaluation for infectious agents, and assessment of nutrient status. Evaluation of the bone marrow should include a search for malignant cells. Cytogenetic abnormalities, if observed, may be helpful in the evaluation but are not definitive.

(6)

The patient must be removed from exposure to benzene and other hematologic toxicants. His home water for drinking and personal purposes should be obtained from a source with no detectable level of benzene. Work exposure to toxic chemicals must be carefully evaluated. Adequate nutrients (vitamins and protein source) in his diet should be assured. Care to prevent injury and bleeding must be exercised until proper blood coagulation (platelets and other factors) has returned, and the patient should be carefully monitored for infection in the event of severe granulocytopenia. Prophylactic antibiotics and blood transfusions should be avoided unless a significant deterioration of his condition becomes evident.

(7)

The prognosis is generally good for the resolution of the macrocytosis. Although this patient has a significant aplastic anemia, it is possible for his bone marrow to recover slowly if the damage has not reached an irreversible stage. Supportive treatment will be needed for many months. Because of the continued risk of leukemia, the patient should receive medical surveillance consisting of regularly scheduled examinations and appropriate testing of hematologic function. The peripheral smear and blood count will permit monitoring of early changes of the patient's condition. Bone marrow biopsy should be repeated in a few weeks to confirm initial findings and observe an expected bone marrow recovery.

(8)

One step in your quest to establish a causal relationship between benzene-contaminated home water and the patient's condition would be to further investigate competing causes of low blood counts for this patient (e.g., drugs, radiation exposure, family history), keeping in mind that most cases of aplastic anemia are idiopathic. You would also need to explore the patient's potential exposure to chemicals other than benzene that might cause hematologic disorders. Finally, assuming the patient's condition is due to benzene exposure, you would need to weigh the significance of benzene sources other than the drinking water. For example, the patient is a diesel mechanic and most likely has inhalation and dermal exposure to gasoline (which contains benzene) at work. You would need to determine the amounts of benzene each source might have contributed to the patient's exposure. (See answer number 1 above.)

For the patient in the case study, as for most exposure cases, it will not be an easy matter to establish causality, and there is no precedent for a person developing hematologic abnormalities from benzene in drinking water.

Case Study

A 14-year-old child, daughter of a dental technician, with cough, wheezing, and low-grade fever

A mother brings her 14-year-old daughter to you for consultation. The patient has developed a troublesome cough and sometimes at night cannot catch her breath. The child's cough has worsened with increase in sputum production and chest discomfort. Last night she had a particularly rough time, but she had no wheezing or fever. Chart review reveals no history of asthma or allergies. The patient's height and weight are appropriate for her age; her two siblings, aged 12 and 6 years, are in good health. History of previous illness reveals three episodes of otitis media but no other significant illness. There is no history of eczema or food intolerance.

In response to your questions, the mother tells you that her husband, a dental technician, has been diagnosed with sarcoidosis. He recently had flu-like symptoms similar to those of his daughter including fatigue, nasal congestion, sneezing, and cough. Although her husband, who smokes cigarettes, has had a cough for several years, the mother states that her daughter developed symptoms a few days after her husband's latest bout. She wonders if her husband's sarcoidosis could have been transmitted to their daughter.

Examination shows a cheerful girl in no acute distress. Her temperature today is 100°F, respiratory rate is 24 without retractions or audible wheezing, and her pulse is 90 and regular. Significant findings include a mildly inflamed pharynx and anterior cervical lymph nodes that are slightly enlarged and mildly tender. Tympanic membranes are clear. Auscultation of the lungs reveals mild and diffuse expiratory wheezing with occasional rhonchi. Results of cardiac and abdominal examinations are normal. Chest X ray shows minimal peribronchial thickening and is otherwise normal.

(a) Construct a problem list and a differential diagnosis for the daughter.

___________________________________________________________________________

(b) What further questions might you ask about the father?

___________________________________________________________________________

(c) What is the most likely diagnosis for the daughter?

___________________________________________________________________________

Answers can be found on page 14 and 15.

Exposure Pathways

❑ Because of its unique properties, beryllium is used in many high-technology consumer and commercial products.

❑ Burning of coal is probably the greatest source of environmental beryllium contamination.

Pure beryllium, one of the lightest metals known, is a hard, grayish material obtained from the mineral rocks bertrandite and beryl. Gem quality beryl is known as either aquamarine or emerald. Although production of beryllium has increased only modestly in the United States in the past 2 decades, the uses of beryllium have expanded. Beryllium has important uses in the defense and electronics industry, especially applications in which fatigue and corrosion resistance, insulation, and nonmagnetic and lightweight qualities are desired.

Occupational exposure to beryllium (as a dust or fume) can occur where it is mined, processed, or converted into metal, alloys, and chemicals. The United States is the leading producer and consumer of beryllium and its alloys. Pure beryllium metal is used in aircraft disc brakes, X-ray components, space-vehicle optics and instruments, aircraft/satellite structures, missile parts, nuclear-reactor neutron reflectors, nuclear weapons, fuel containers, precision instruments, rocket propellants, navigational systems, heat shields, and mirrors. Beryllium alloys also have many uses, including electrical connectors and relays, springs, precision instruments, aircraft engine parts, nonsparking and nonmagnetic tools, computers, ceramics, submarine cable housings and pivots, wheels and pinions, and dental castings. Dental prostheses are shaped by grinding the structural elements, which are often made of beryllium alloy.

Beryllium oxide is the material of choice for many high-technology applications in which heat resistance is imperative. Applications include ceramics, electronic heat sinks, electrical insulators, microwave oven components, gyroscopes, military vehicle armor, rocket nozzles, crucibles, thermocouple tubing, and laser structural components.

Although beryllium is a naturally occurring substance, the major source of its emission into the environment is the combustion of fossil fuels (primarily coal), which releases beryllium-containing particulates and fly ash into the atmosphere. The open pits in Utah, where bertrandite is mined, also cause high airborne levels locally. Mantles of some camping lanterns emit small amounts of beryllium during initial use. Tobacco smoke also is a minor source of beryllium exposure. Beryllium is relatively water insoluble and adsorbs tightly to soils. It has been found in various foodstuffs, but bioaccumulation in the food chain is not significant.

Who's at Risk

❑ Most significant exposures to beryllium occur in the occupational setting.

❑ A small percentage of the population is hypersensitive to beryllium.

❑ Chronic beryllium disease has been reported recently in a household contact of a beryllium worker.

There are no accurate estimates of the number of workers exposed to beryllium; however, we know that workers potentially exposed are those engaged in smelting, metal machining, and reclaiming scrap alloys, as well as those in high-technology industries such as aerospace, nuclear, telecommunications, and computer industries. The mining of beryllium ore has not been associated with beryllium disease (acute or chronic); however, the relationship has not been studied systematically. Inhaling metallic beryllium, beryllium oxide, beryllium-copper alloys, or beryllium salts can cause beryllium disease.

Beryllium disease was first noted in the 1930s in workers exposed to beryllium-containing phosphors in the fluorescent lamp industry. Industry standards and environmental controls for beryllium were established in the 1950s. Although acute beryllium disease occurs rarely today, chronic beryllium disease (berylliosis) continues to occur in industries where beryllium and its alloys are smelted, fabricated, and machined. The terms acute and chronic, used to describe beryllium disease, refer to disease processes, rather than types of exposure. Acute beryllium disease manifests as pulmonary inflammation, whereas chronic beryllium disease is typically a progressive pulmonary granulomatosis.

Low, seemingly trivial exposures to beryllium may be important in causing beryllium disease. Chronic beryllium disease has been found in persons living near a plant using beryllium, although neighborhood cases have decreased considerably since industry control measures were instituted. As recently as 1991, a case of chronic beryllium disease due to secondary contamination was reportedly caused by a family member's exposure to beryllium from a worker's clothing.

A small percentage of exposed persons (1% to 3%) develop beryllium hypersensitivity and chronic disease. (Hypersensitivity to beryllium can be demonstrated by in vitro proliferative responses of lymphocytes obtained through blood or bronchoalveolar lavage.) Some workers manifest this cellular immune response even if they work in areas where beryllium air concentrations are found to be below the recommended workplace exposure limits. Sensitization has been reported in security guards, secretaries, and custodial staff who work at facilities using beryllium.

No correlation has been found between smoking and increased incidence of beryllium disease. However, inhalation of beryllium does appear to alter the ability of the lungs to clear other inhaled agents.

Biologic Fate

❑ Inhaled beryllium is solubilized in the lungs and distributed primarily to bone, liver, and kidneys.

❑ Contact of beryllium with broken skin can lead to systemic absorption.

❑ Most beryllium is excreted in the urine.

Beryllium exposure occurs primarily by inhalation and contact through broken skin. After inhalation, particles containing beryllium are deposited in the respiratory tract, solubilized upon contact with respiratory epithelium, and absorbed into the bloodstream. Solubilized beryllium may bind to the phosphate in plasma proteins, forming a complex that is engulfed by macrophages. The pulmonary half-life of beryllium ranges from several weeks to 6 months, although beryllium has been detected in the lungs of persons with chronic beryllium disease decades after the exposure has ceased.

Ingested beryllium is presumed to be solubilized in the acidic milieu of the stomach and absorbed predominantly from the stomach. Beryllium absorption rates vary widely and correspond to gastric emptying time. In the intestinal fluid, a beryllium-protein complex forms and is eliminated. Ingested beryllium is not thought to be associated with disease.

Beryllium is not absorbed through intact and uninjured skin. However, significant amounts can be absorbed dermally through burns, abrasions, and open wounds. Local deposition and systemic absorption can result from accidental inoculation by beryllium splinters.

Beryllium and its compounds are not biotransformed but remain as Be⁺² in the body. The highest levels of beryllium are found in bone; lesser amounts are distributed to the liver and kidneys. Placental crossing occurs only to a small extent.

Inhaled or ingested beryllium is excreted slowly. The renal system removes more than 90% of absorbed beryllium, but less than 1% is excreted within the first day. Plasma beryllium does not cross the glomerular membrane and is eliminated through the renal tubules. Levels in the urine are highly variable due to differing compartmental clearance rates; beryllium can take months to years to be removed from pulmonary lymph nodes and bone. The metal has been found in the urine as long as 10 years after cessation of exposure.

Physiologic Effects

Clinical Evaluation

Differential Diagnosis

❑ Chronic beryllium disease continues to be misdiagnosed as sarcoidosis.

The differential diagnosis for interstitial and granulomatous lung disease is long. Conditions that may resemble chronic beryllium disease include tuberculosis, fungal disease, asbestosis, silicosis, hypersensitivity pneumonitis, pulmonary hemosiderosis, lymphangitic spread of carcinoma, and sarcoidosis. Of these, the clinical features of sarcoidosis are most similar to the characteristics of chronic beryllium disease (Table 1). Although each disease possesses characteristic clinical features, no feature has proved adequately sensitive and specific to be pathognomonic. Chronic beryllium disease tends to have less prominent extrapulmonary manifestations. For example, to date, no patient with chronic beryllium disease has developed uveitis, uveoparotid fever, cranial or peripheral nerve involvement, or cystic bone lesions—conditions that have affected patients with sarcoidosis. Furthermore, chronic beryllium disease is progressive and often requires lifelong corticosteroid therapy to slow its course. Spontaneous remission of chronic beryllium disease has been reported to occur after cessation of exposure, but this is rare.

Table 1.

Comparison of clinical features— sarcoidosis and chronic beryllium disease.

Treatment and Management

❑ Corticosteroid therapy is the primary treatment modality for chronic beryllium disease.

❑ An estimated 30% of patients with chronic beryllium disease die from complications directly attributable to their disease.

Although there is little scientific evidence that cessation of exposure alters the course of beryllium disease once it is manifest, exposure cessation should be the first goal of management. For patients with chronic beryllium disease, corticosteroid therapy is the primary treatment modality. Corticosteroids provide symptomatic relief and improve lung function; they are required lifelong for most patients. When symptoms are controlled, an alternate day, single-dose regimen can be tried. Alternate-day doses usually range from 20 mg to 40 mg prednisone; occasionally up to 80 mg is required for short periods. More aggressive disease may require even higher daily doses of corticosteroids. There is no cure, and spontaneous remissions occur rarely.

Supplemental oxygen may be necessary to correct hypoxemia associated with chronic beryllium disease. Right ventricular failure and its complications are late-stage sequelae. Severe cough may require restricting physical activity. Pneumothorax can occur. Emphysema and pulmonary fibrosis, which are common in long-term disease, can prove poorly responsive to corticosteroids. As with chronic lung disease of other etiologies, one should be vigilant for bacterial respiratory infections and should treat infections promptly with antibiotics when indicated. Patients should be immunized against pneumococcus and influenza and counseled to avoid exposures to other substances that cause lung injury, including cigarette smoke.

Responses to therapy vary. In some cases, the disease symptoms appear mild at diagnosis, progress minimally, and are controlled well with corticosteroids. In others, the course is increasingly severe and controlled poorly by corticosteroids. Reviewers of 130 pathologic specimens obtained from patients in the U.S. Beryllium Case Registry concluded that the greater the degree of interstitial infiltration present, the worse the clinical course and prognosis. Persons demonstrating a predominance of well-formed granulomas and minimal interstitial fibrotic changes had a more benign course and better prognosis. Investigators found no correlation between histology and responsiveness to steroids, nor between length of the latency period and type of histology manifested. It is estimated that 30% of patients with chronic beryllium disease die from complications directly attributable to their disease.

Careful irrigation and débridement are recommended for wounds potentially contaminated with beryllium. Complete excision is curative for beryllium-contaminated injury sites that demonstrate delayed healing, ulceration, and granuloma formation. The main treatment for contact dermatitis associated with beryllium salt exposure is cessation of exposure.

Standards and Regulations

The standards and regulations for beryllium are summarized in Table 2. EPA considers beryllium a probable human carcinogen.

Table 2.

Standards and regulations for beryllium.

Suggested Reading List

• Aronchick JM, Rossman MD, Miller WT. Chronic beryllium disease: diagnosis, radiographic findings, and correlation with pulmonary function tests. Radiology 1987; 163:677–82. [PubMed: 3575713]
• Cullen MR, Cherniak MG, Kominsky JR. Chronic beryllium disease in the United States. Semin Respir Med 1986; 7:203–9.
• Cullen MR, Kominsky JR, Rossman MD, et al. Chronic beryllium disease in a precious metal refinery: clinical epidemiologic and immunologic evidence for continuing risk from exposure to low-level beryllium fume. Am Rev Respir Dis 1987; 135:201– 8. [PubMed: 3492158]
• Daniele RP, Elias JA, Epstein PE, Rossman MD. Bronchoalveolar lavage: role in the pathogenesis, diagnosis, and management of interstitial lung disease. Ann Intern Med 1985; 102:93–108. [PubMed: 3881071]
• Epstein PE, Dauber JH, Rossman MD, Daniele RP. Bronchoalveolar lavage in a patient with chronic berylliosis: evidence for hypersensitivity pneumonitis. Ann Intern Med 1982; 97:213–6. [PubMed: 7103279]
• Hardy HL Beryllium disease: a clinical perspective. Environ Res 1980; 21:1–9. [PubMed: 6993204]
• Jones-Williams W. Beryllium disease. Postgrad Med J 1988; 64:511–6. [PMC free article: PMC2428897] [PubMed: 3074283]
• Jones-Williams W. On the differential diagnosis of chronic beryllium disease and sarcoidosis [Letter]. Am Rev Respir Dis 1990; 142(3):739. [PubMed: 2389922]
• Kreiss K, Newman LS, Mroz MM, Campbell PA. Screening blood test identifies subclinical beryllium disease. J Occup Med 1989; 31:603–8. [PubMed: 2788726]
• Kriebel D, Brain JD, Sprince NL, Kazemi H. The pulmonary toxicity of beryllium. Am Rev Respir Dis 1988; 137:464–73. [PubMed: 3277503]
• Mroz MM, Kreiss K, Lezotte DC, Campbell PA, Newman LS. Reexamination of the blood lymphocyte transformation test in the diagnosis of chronic beryllium disease. J Allergy Clin Immunol 1991; 88:54–60. [PubMed: 2071785]
• Newman LS, Kreiss K, King TE Jr, Seay S, Campbell PA. Pathologic and immunologic alterations in early stages of beryllium disease: re-examination of disease definition and natural history. Am Rev Respir Dis 1989; 139:1470–86. [PubMed: 2729754]
• Rom WN, Lockey JE, Lee JS, et al. Pneumoconiosis and exposures of dental laboratory technicians. Am J Public Health 1984; 74:1252–7. [PMC free article: PMC1652029] [PubMed: 6496819]
• Rossman MD, Kern JA, Elias JA, et al. Proliferative response of bronchoalveolar lymphocytes to beryllium: a test for chronic beryllium disease. Ann Intern Med 1988; 108:687–93. [PubMed: 3282464]
• Saltini C, Winestock K, Kirby M, et al. Maintenance of alveolitis in patients with chronic beryllium disease by beryllium-specific helper T cells . N Engl J Med 1989; 320:1103–9. [PubMed: 2469014]

Government Publications

• Agency for Toxic Substances and Disease Registry. Toxicological profile for beryllium. Atlanta: US Department of Health and Human Services, Public Health Service, 1988. Report no. ATSDR/TP-88/07.
• Environmental Protection Agency. Health assessment for beryllium. Washington, DC: US Environmental Protection Agency, 1988. Report no. PB88–179205.
• Environmental Protection Agency. Health effects assessment for beryllium and compounds. Cincinnati: US Environmental Protection Agency, Environmental Criteria and Assessment Office, 1988. Report no. PB88–179460.

Answers to Pretest and Challenge Questions

Sources of Information

More information on the adverse effects of beryllium and treating and managing cases of exposure to beryllium can be obtained from ATSDR, your state and local health departments, and university medical centers. Case Studies in Environmental Medicine: Beryllium Toxicity is one of a series. For other publications in this series, please use the order form on the back cover. For clinical inquiries, contact ATSDR, Division of Health Education, Office of the Director, at (404) 639–6204.

Case Study

Low back pain and waddling gait in a 60-year-old woman

A 60-year-old woman comes to your office with complaints of low back pain, which is causing progressive difficulty in walking. The pain has gradually increased since the onset of menopause 5 years ago. This discomfort is especially noticeable after prolonged sitting.

Social history reveals that the patient has been a housewife since her marriage 38 years ago. Her husband, who is in good health, owns and operates a small retail shop in their home. The patient has been making jewelry for sale in her husband's shop and as a hobby for about 35 years. They have two adult sons who are in good health.

The patient denies a personal or family history of kidney disease, hypertension, diabetes mellitus, or cardiovascular disease; she also denies history of back trauma or weight loss. She has smoked one to two packs of cigarettes a day for the past 40 years. She does not take estrogens, calcium supplements, vitamins, or other medications.

On examination you find a thin female with a slightly stooped posture and a waddling gait. Blood pressure is 120/70. Her teeth have a yellow discoloration above the crown, and her fingernails are stained with nicotine. She is anosmic on cranial nerve examination. Results of cardiovascular and abdominal examination are normal. The lower lumbar spine is tender to percussion, but the patient does not complain of pain on straight leg raising. Her deep tendon reflexes are intact, and the remainder of the physical examination, including neurologic testing, is normal. Sensation and strength are normal in legs and feet. Range of motion is normal in hips and knees.

Initial laboratory data include a urinalysis showing 3⁺ proteinuria and glycosuria. BUN, creatinine, and albumin levels are normal. Roentgenograms of the pelvis and lumbosacral spine reveal pseudofractures and other evidence of severe osteomalacia and mild osteoporosis. There are no osteolytic or osteoblastic lesions.

(a) What should be included on the patient's problem list?

_________________________________________________________________

(b) What additional information would be helpful in diagnosing this woman's condition?

_________________________________________________________________

(c) What further tests, if any, would you recommend?

_________________________________________________________________

(d) What treatment would be appropriate for this patient?

_________________________________________________________________

Answers to the Pretest are included in Challenge answers (6) through (9) on page 19.

Exposure Pathways

❑ In the general population, exposure to cadmium occurs primarily by eating crops grown in contaminated soil and seafood.

❑ Airborne cadmium sources include combustion of fossil fuels, incineration of municipal waste, and smelter emissions.

Pure cadmium is a silver-white, lustrous metal, but cadmium in this form is not common in the environment. It is most often encountered in the earth's crust combined with chlorine (cadmium chloride), oxygen (cadmium oxide), and sulfur (cadmium sulfide). Cadmium oxide also exists as small particles in air (fume), the result of smelting, soldering, or other high-temperature industrial processes. Most cadmium used in the United States is obtained as a byproduct of the smelting of zinc, lead, or copper ores. Cadmium is used mainly in metal plating; in producing pigments, batteries, and plastics; and as a neutron absorbant in nuclear reactors.

Foods are the most important source of cadmium exposure for the general population. Low levels of cadmium are found in basic foodstuffs, especially grains, cereals, and leafy vegetables, which readily absorb naturally occurring cadmium or cadmium in soil contaminated by sewage sludge, fertilizers, and polluted groundwater. In 1946, the inhabitants of the Jintzu River basin in Japan were afflicted with a disease characterized by pain and bone fractures (called itai-itai or ouch-ouch disease), which was caused by high levels of cadmium in water and rice, the result of using water contaminated by discharges from a local zinc-mining operation. Cadmium bioaccumulates in the food chain; consequently, ingestion of animal internal organs, such as liver and kidneys, and some types of fish and shellfish may result in increased exposure.

The greatest sources of airborne cadmium are burning fossil fuels such as coal or oil, and incineration of municipal waste such as plastics and nickel-cadmium batteries. Cadmium may also escape into the air from zinc, lead, or copper smelters, and from iron and steel production facilities. Like most plants, tobacco contains cadmium, which is inhaled in cigarette smoke.

Cadmium concentrations in drinking water supplies are typically less than 1 microgram per liter (µg/L) or 1 part per billion (ppb). Groundwater seldom contains high levels of cadmium unless it is contaminated by mining or industrial wastewater, or seepage from hazardous waste sites. Soft or acidic water tends to dissolve cadmium and lead from water lines; cadmium levels are increased in water stagnating in household pipes. These sources have not caused clinical cadmium poisoning, but even low levels of contamination presumably contribute to the body's accumulation of cadmium.

Cadmium is a component of chuifong tokwan, a pharmaceutical compound manufactured in Asia and sold illegally in the United States as a “miracle herb.” Some artists' paints contain a yellow pigment made from cadmium sulfide. Cadmium at one time was a leachable component of the alloy used in ice cube trays.

Who's at Risk

❑ Workers in industries producing or using cadmium have the greatest potential for cadmium exposure; hobbyists such as jewelry fabricators and artists may also be at increased risk.

❑ Cigarette smoke may add to the body's cadmium burden.

❑ Cadmium absorption may be increased in nutritionally deficient persons.

Background levels of cadmium in food, water, and ambient air are not a health concern for the general North American population. Typical dietary intake is about 30 micrograms of cadmium per day (30 µg/day), a rate roughly ten times lower than that required to cause critical renal effects. Acute cadmium toxicity is rare because very high levels are seldom encountered in the workplace today, and low doses are not acutely toxic. An acute oral dose of 50 µg/kilogram (kg) body weight (about 3500 µg in an adult) is considered the minimal amount capable of causing gastric irritation. Chronic exposures, however, can be a major concern because cadmium has a tendency to accumulate in the body.

Persons in the United States at greatest risk of cadmium exposure are 500,000 workers, including the following:

Alloy makers

Aluminum solder makers

Ammunition makers

Auto mechanics

Battery makers

Bearing makers

Braziers and solderers

Cable, trolley wire makers

Cadmium platers

Cadmium vapor lamp makers

Ceramics, pottery makers

Copper-cadmium alloy makers

Dental amalgam makers

Electric instrument makers

Electrical condenser makers

Electroplaters

Engravers

Glass makers

Incandescent lamp makers

Jewelers

Lithographers

Lithopone makers

Mining and refining workers

Paint makers

Paint sprayers

Pesticide makers

Pharmaceutical workers

Photoelectric cell makers

Pigment makers

Plastic products makers

Sculptors, metal

Smelterers

Solder makers

Textile printers

Welders, cadmium alloy and cadmium-plate

Hobbyists may also encounter cadmium in their pursuits. For example, cadmium is present in many gold and silver solders used in fabricating jewelry and in the metal dust produced in grinding or engraving cadmium-plated surfaces. The likelihood of cadmium inhalation is increased in poorly ventilated work areas, and cadmium ingestion is increased by eating and smoking in these areas.

Cadmium air levels are usually thousands of times greater in the workplace than in the general environment. For example, the permissible exposure limit (PEL) of cadmium fume or cadmium oxide in the workplace is 100 micrograms per cubic meter of air (100 µg/m³), whereas concentrations of cadmium in ambient air rarely exceed 0.0025 µg/m³ in nonindustrialized areas and 0.040 µg/m³ in urban areas. The U.S. Environmental Protection Agency (EPA) has estimated that 24-hour, lifelong inhalation of air containing 1 µg/m³ cadmium is associated with a lung cancer risk of, at most, 2 additional cases in 1000 persons exposed.

Each cigarette contains 2 µg of cadmium, with 50% absorbed from the lungs during active cigarette smoking. Persons who smoke one pack per day typically have cadmium blood and body burdens approximately twice as high as those of nonsmokers.

Nutritional factors affect the amount of cadmium absorbed. Persons with low calcium, protein, or iron reserves absorb cadmium more efficiently and may be at increased risk of developing toxicity. Age and gender may also play a role. Iron-deficient neonates absorb greater amounts of cadmium than iron-deficient adults; females absorb more than males. Iron deficiency, resulting in increased cadmium absorption, may have contributed to the high incidence of itai-itai disease in multiparous Japanese women.

Biologic Fate

❑ Cadmium has no known beneficial function in the human body.

❑ Cadmium is transported in the blood bound to metallothionein.

❑ The greatest cadmium concentrations are found in the kidneys and the liver.

Respiratory absorption of cadmium in humans is estimated to be from 30% to 60% of an inhaled dose, depending on particle size. Only the smallest particles penetrate to the alveoli, the major site of absorption. As a result, cadmium particles in fumes and cigarette smoke, which are smaller, are more completely absorbed than most cadmium particles of industrial origin.

In humans, no more than 5% of ingested cadmium is absorbed from the gut into the blood or lymphatic fluid. Although some nutritional factors increase this absorption, zinc and chromium can decrease cadmium uptake. Absorption through the skin is not a significant route of cadmium entry.

❑ Urinary cadmium excretion is slow; however, it constitutes the major mechanism of elimination. Cadmium biologic half-life may be up to 30 years.

Once absorbed, cadmium is distributed by the blood. Lymphocytes synthesize metallothionein, a metal-binding protein, which concentrates cadmium three-thousandfold. Cadmium does not undergo metabolic conversion in vivo.

Cadmium is eliminated from the body primarily in urine. The rate of excretion is low, probably because cadmium remains tightly bound to metallothionein, which is almost completely reabsorbed from the glomerular filtrate. Because excretion is slow, cadmium accumulation can be significant. Whereas cadmium concentration in blood reflects recent exposure, urinary cadmium concentration more closely reflects total body burden. However, when renal damage from cadmium exposure occurs, the excretion rate increases sharply, and urinary cadmium levels no longer reflect body burden.

The total cadmium body burden at birth is less than 1 µg, which gradually increases with age to about 30 milligrams (mg). The highest cadmium concentration is found in the kidneys, especially the renal cortex, followed by the liver, pancreas, and adrenals. In the kidney, cadmium concentration steadily increases overtime, then declines at 50 to 60 years of age. In the liver, however, cadmium concentration increases continuously with age. The kidneys and liver together total about 50% of the body accumulation in humans.

Both the liver and kidneys store cadmium as a metallothionein complex, which serves not only to transport cadmium but also acts as a defense mechanism against the toxicity of the unbound cadmium ion. Ironically, it is the cadmium-metallothionein complex that accumulates in the kidneys and is partially responsible for cadmium's toxic renal effects. Cadmium does not accumulate in bone, and the blood-brain barrier appears to limit its uptake into the central nervous system. The placenta acts only as a partial barrier to fetal exposure.

The biologic half-life of cadmium in the body is estimated to be 30 years. This long half-life is due to the body's inability to deal with increasing cadmium intake by homeostatic control mechanisms; humans do not have an effective cadmium elimination pathway. Cadmium has no known biologic function in humans, and bioaccumulation appears to be a byproduct of increasing industrialization. Any excessive accumulation in the body should be regarded as potentially toxic.

Physiologic Effects

❑ Cadmium primarily affects the kidneys and skeletal system.

The mechanisms of cadmium toxicity are not fully understood but may involve binding of the metal to key cellular sulfhydryl groups, competition with other metals (zinc and selenium) for inclusion in metalloenzymes, and competition with calcium for binding sites on regulatory proteins such as calmodulin. The route and extent of cadmium exposure will influence the presentation of toxic effects.

Clinical Evaluation

Treatment and Management

One exposed person often signals potential or actual exposure of others, with the possibility of a common exposure source. Such sources include the workplace, drinking water supply, community irrigation, proximity to a smelter, and so on. Public health authorities should be notified whenever cadmium toxicity is suspected in a patient so that case-finding may be initiated and preventive measures taken.

Standards and Regulations

With increasing evidence of its toxicity, both national and international agencies have sought to regulate cadmium exposure. These efforts encompass workplace and environmental guidelines or regulations for air emissions, drinking water, food, industrial discharges, and hazardous waste concentrations. Table 1 summarizes standards, regulations, and guidelines for cadmium.

Table 1.

Standards and regulations for cadmium.

Suggested Reading List

Answers to Pretest and Challenge Questions

Pretest is found on page 1. Challenge questions begin on page 5.

(1)

Potential sources of cadmium are as follows:

(a)

cadmium fume (cadmium oxide) generated by use of gold and silver solders during jewelry fabrication

(b)

cadmium dust produced in smoothing jewelry with abrasive grinding or in engraving cadmiumplated surfaces

(c)

food and cigarettes in the workplace contaminated by cadmium-containing participates and dust

(d)

cigarette smoke

(e)

food grown in soil contaminated with cadmium-containing fertilizer obtained from the wastewater treatment plant

(2)

Risk factors are due to not only increased opportunity for cadmium exposure, but age and nutritional status as well. The patient's hobby, jewelry fabrication, may provide low-to-moderate chronic cadmium exposure. Lack of respiratory protection, poor ventilation, and poor hygiene in the work area increase the amount of her exposure. The patient also inhales approximately 2 µg cadmium with each cigarette smoked. The amount of cadmium ingested from the vegetables grown in her garden is unknown, but sludges from wastewater treatment plants have been found to contain significant levels of cadmium. Factors that may enhance cadmium absorption from the gut are age and certain dietary deficiencies.

(3)

Yes, the patient's husband also may be at increased risk of cadmium toxicity because of increased opportunity for exposure, although his risk is probably less than his wife's. The husband is exposed to cadmium by eating food from the contaminated garden and by inhaling tobacco smoke from cigarettes, even more so if he smokes. In the basement work area, he may encounter cadmium fumes and dust as a result of his wife's hobby. He also may be exposed to the cadmium on his wife's clothing and skin if she does not shower and change clothes before leaving the work area.

(4)

Yes, diet could play an important role in the patient's condition, both for what it contributes and for what it does not include. For example, the homegrown vegetables from the garden, particularly leafy vegetables, and animal liver or kidney and shellfish could be contributing to her cadmium burden. If her diet is deficient in iron, calcium, or protein she may be absorbing cadmium more efficiently.

(5)

The patient's problem list includes the following:

back pain

severe osteomalacia and mild osteoporosis

pseudofractures

yellow discoloration of the teeth

proteinuria and glycosuria

All of these are consistent with chronic cadmium toxicity. The patient is also a smoker. Chronic cadmium exposure primarily affects the kidneys and skeleton. Renal dysfunction in this patient is indicated by the laboratory findings. The stooped posture, waddling gait, lumbar pain, and pain induced by spinal percussion are the result of skeletal changes and deformities.

(6)

Most of your questions will probably center on the patient's hobby, as this is the greatest potential source of cadmium exposure. Typical questions would include the following:

(a)

What types of materials and metals are used in making jewelry? What are the ingredients of all composite products?

(b)

On a weekly basis, how many hours are spent fabricating jewelry in the basement?

(c)

What type of face shield is used? Why is respiratory protection not used during grinding and soldering operations?

(d)

Is the work area kept clean and free of dust? How?

(e)

Does she wash her hands before eating in the work area and are attempts made to keep food and cigarettes from becoming contaminated by dust and particulates?

(f)

Does she shower and change her clothes before leaving the work area?

It is also important to investigate smoking habits.

(7)

The most useful diagnostic test for cadmium exposure is a 24-hour urinary cadmium excretion standardized for creatinine: ß₂-microglobulin levels, in conjunction with cadmium excretion, will aid in evaluating subclinical renal dysfunction. The following tests also may be helpful in evaluating the patient: urinary protein and glucose, LDH, SGPT or ALT, and SGOT or AST. A chest X ray and pulmonary function test should be obtained if cadmium inhalation is a factor.

(8)

The patient is experiencing renal dysfunction, as evidenced by the 3⁺ level of proteinuria and glycosuria. When proximal tubular damage occurs, cadmium excretion can result from two sources; breakdown of the tubular epithelium and decreased reabsorption. Under these conditions, urinary cadmium levels are likely to be markedly increased and no longer reflect body burden. Exposed workers can excrete several hundred micrograms of cadmium per gram of creatinine; urinary cadmium levels in an unexposed population are typically between 1 and 10 µg cadmium/g creatinine. The patient therefore would be expected to have a urinary cadmium level of several hundred micrograms of cadmium per gram of creatinine, depending on her most recent exposure.

(9)

There is no effective treatment for cadmium toxicity; chelation therapy has no role in cadmium poisoning. Removal from the source of exposure and patient education to significantly reduce exposure are important, particularly before the condition has progressed to irreversible renal dysfunction. Supportive measures to alleviate symptoms should be provided.

10)

The neighbors should be evaluated and educated. Even if they do not use the fertilizer from the wastewater treatment plant or water from the same irrigation source, runoff from the patient's land may contaminate their soil or well water. Consultation with the local or state health department is advisable if a potential public health hazard exists.

Case Report

A 20-year-old white female arrived by ambulance at the hospital approximately 60 min after being found unconscious at her mobile home. She had been intubated by the Emergency Medical Services and had received 100% supplemental oxygen en route to the hospital. The patient's 21-year-old husband was also found at the scene and brought to the hospital. Although initially disoriented, restless, and combative, he was lucid at the time of arrival in the emergency department. From his history, it was determined that the couple's usual heater was in disrepair, and a portable propane heater was the sole source of heat in their unventilated mobile home. He also disclosed that his wife was 28 weeks into her first pregnancy, that her past medical history was unremarkable, and that she was not currently taking medications or using cigarettes.

During the initial physical examination, the patient was noted to be combative and confused. Her blood pressure was palpable by cuff measurement at 80 torr systolic. She was being ventilated by a volume-cycled ventilator which she triggered 26 times a minute. Carbonaceous material was found in the nares, oropharynx, and adherent to the endotracheal tube. No burns of the skin, nasal hair, face, or eyebrows were present. Abdominal examination results were consistent with a 28-week intrauterine pregnancy.

No fetal movement could be detected by ultrasound, and fetal heart sounds were absent. Peripheral cyanosis was noted in her nail beds. The measured carboxyhemoglobin concentration at the time of admission was 7%. A plasma and urine toxicology screen was negative. The initial chest radiograph was interpreted as showing bilateral alveolar infiltrates consistent with the adult respiratory distress syndrome.

On the second hospital day, the patient went into labor spontaneously and delivered a 1050-g stillborn female fetus of approximately 7 months gestation, with a crown-heel length of 39 cm and crown-rump length of 27 cm. The gross autopsy findings were remarkable only for bright red discoloration of the skin and visceral organs. The corrected fetal COHb saturation at the time of the autopsy was 61% by IL 282-CO-Oximeter³ [ 4 ]. On microscopic examination of the tissues, the expected autolytic changes were seen but no other diagnostic abnormalities were found.

The mother began a slow convalescence after delivery of the fetus and subsequently recovered normal pulmonary function. She was discharged on the ninth hospital day.

Discussion

Approximately 3500 to 4000 deaths each year in the United States are caused from carbon monoxide (CO), the nonirritating, odorless, tasteless, and colorless inert gas that is produced by the incomplete combustion of carbon-containing materials [ 1 ].

CO has an affinity for reversibly binding with adult hemoglobin that is 250 times greater than that of oxygen [ 5 ]. Measurement of the carboxyhemoglobin (COHb) level provides the clinician with an objective parameter to correlate with clinical symptoms and prognosis. Because CO is endogenously produced in humans during metabolism of protoporphyrin to bilirubin during hemoglobin metabolism, a nonsmoking individual may have a normal resting COHb saturation of 1 to 3% [ 6 ]. Cigarette smokers will commonly have COHb levels of 5 to 6%, and, if they smoke continuously, COHb levels may reach 8 to 10% [ 7 ].

CO interferes with cellular metabolism by inhibiting the transport, delivery, and utilization of oxygen. CO successfully competes for oxygen binding sites. The hemoglobin molecule will then bind more avidly to the oxygen molecules on its surface, resulting in a shift of the oxyhemoglobin dissociation curve to the left. Finally, CO poisons cellular respiration by displacing oxygen from receptors of the cytochrome oxidase system, particularly cytochrome a3 and cytochrome P-450 [ 6 ].

In adults, COHb concentrations of 30 to 40% are generally associated with weakness, dizziness, nausea and vomiting, and cardiovascular collapse. Syncope, seizures, and death may occur with COHb levels of 50% [ 8 ]. Inhalation of ambient gas which has a CO concentration of 1% can be fatal within 10 min, depending on the victim's activity and respiratory rate [ 9 ]. Likewise, victims with underlying diseases such as anemia, heart dysfunction, or lung disease may succumb at much lower COHb concentrations [ 7 ].

Interestingly, Goldbaum [ 10 ] has shown that CO is toxic only when inhaled through the lungs and not when introduced by intraperitoneal injection or transfusion with CO-saturated red cells. He asserts that the toxic effects of CO are not caused by elevated COHb alone, such as occurs in the latter two instances, but also by direct action of dissolved CO on the cytochrome oxidase system. Thus, he cautions that COHb determination may be misleading without knowledge of environmental conditions and the respiratory status of the individuals affected.

Investigations of CO exchange between mother and fetus have shown that CO absorption and elimination occur more slowly in the fetal circulation [ 11 , 12 ]. Following maternal exposure to CO, the fetal COHb rises more slowly than the maternal COHb but will continue to rise for several hours after acute exposure until it eventually reaches an equilibrium at a level which is approximately 10% greater than the mother's COHb saturation [ 12 ]. The pattern of elimination of CO is similar, and fetal COHb concentrations diminish more slowly than maternal COHb levels [ 13 ]. Although there is some evidence that the placenta has some capacity to transport CO actively, passive diffusion through the placenta along a partial pressure gradient is thought to account for the bulk of fetal CO absorption and elimination [ 14 ].

Our case further illustrates the differing CO kinetics between the maternal and fetal circulations. The normal COHb half-life of 4 to 5 h when breathing room air with an oxygen concentration of approximately 21%, can be markedly shortened by inhaling oxygen at higher concentrations. If 100% supplemental oxygen is administered, the COHb half-life is shortened to 60 min [ 8 ]. Approximately 40 to 50% of the body's CO can be eliminated in 1 h when high fractions of oxygen are rapidly administered by emergency rescue teams [ 7 ]. Unfortunately, it is estimated that it takes four to five times as long for the fetal COHb to decrease to the same maternal COHb level [ 14 ]. The implications for treatment of the pregnant victim are clear.

Fetal tissues are at greater risk from hypoxia caused by CO since a higher COHb equilibrium is achieved, COHb elimination is delayed, and the fetal hemoglobin experiences a more accentuated left shift than does adult hemoglobin [ 15 ]. This particular susceptibility of fetal tissue to CO toxicity has promoted interest in utilizing hyperbaric oxygen for the treatment of the pregnant patient with CO poisoning. With the use of 100% oxygen at 2 to 3 atmospheres of pressure, the COHb elimination can be significantly enhanced in both mother and fetus [ 14 ]. In lieu of this modality, supplemental oxygen at concentrations approaching 100% should be administered for five times the length of time needed to reduce the maternal COHb to acceptable concentrations [ 14 ].

The mother in our report is assumed to have reached a minimal COHb concentration of 40 to 50% since she sustained loss of consciousness. Therefore, with the kinetics described, the fetus would be expected to develop a COHb level of at least 65%. To explain the disparity between maternal and fetal COHb concentrations in our case, it is necessary to postulate that fetal death occurred at the time that the fetal circulation reached its maximal COHb saturation. According to available research information, the fetal COHb concentration is not expected to change after death in utero. CO is not produced by decomposition, nor is it absorbed in significant amounts by a body when exposed to an environment rich in CO. Indeed, COHb persists for weeks in the human body and may be accurately quantified even after embalming and burial [ 7 ].

In chronic or nonfatal CO poisoning, degenerative changes can often be seen involving the basal ganglia, kidneys, liver, and heart. These lesions are indicative of severe tissue hypoxia and are not pathognomonic of CO poisoning [ 9 ]. In acute asphyxia due to CO, death occurs before these lesions can develop. The fetal autopsy suggested COHb poisoning by the cherry red discoloration of the skin and visceral organs.

The carboxyhemoglobin concentration that causes fetal death in humans has not yet been defined. The clinician's ability to predict fetal survival is poor because the fetal COHb concentration cannot be estimated from a single determination of maternal concentration without knowledge of the maternal exposure pattern. At the present time, the best predictive index of fetal morbidity and mortality appears to be the severity of maternal symptoms at the site of exposure.

The authors hope that this account of fetal death associated with nonfatal maternal exposure to CO, which is only the second report to include measurement of both maternal and fetal COHb saturations, will alert both death investigators and clinicians to the fragile relationship that exists between mother and fetus under circumstances of CO exposure.

References

• [ 1 ] Centers for Disease Control, “Carbon Monoxide Intoxication—A Preventable Environmental Health Hazard,” Morbidity and Mortality Weekly Report , Vol. 31,1982, pp.529–531. [PubMed: 6817049]
• [ 2 ] Finck, P.A., “Exposure to Carbon Monoxide,” Forensic Medicine: A Study in Trauma and Environmental Hazards , C.G.Tedeschi, editor; , W.G.Eckert, editor; , and L.G.Tedeschi, editor. , Eds., W.B. Saunders Co., Philadelphia, PA, 1977.
• [ 3 ] Cramer, C.R., “Fetal Death Due to Accidental Maternal Carbon Monoxide Poisoning,” Journal of Toxicology: Clinical Toxicology , Vol. 19, No. 3 , 1982, pp.297–301. [PubMed: 7131616]
• [ 4 ] Cornellison, P.J.H., Van Woensel, C.L.M., Van Oel, W.C., and de Jong, P.A., “Correction Factors for Hemoglobin Derivatives in Fetal Blood, as Measured with the IL-282 CO-Oximeter,” Clinical Chemistry , Vol. 29, No. 8 , 1983, pp.1555–1556. [PubMed: 6872224]
• [ 5 ] Winter, P.M. and Miller, J.N., “Carbon Monoxide Poisoning,” Journal of the American Medical Association , Vol. 236, No. 13 , 27 Sept. 1976, pp.1502–1504. [PubMed: 989121]
• [ 6 ] Myers, R.A.M., Linberg, S.E., and Cowley, R.A., “Carbon Monoxide Poisoning: The Injury and Its Treatment,” Journal of the American College of Emergency Physicians , Vol. 8, No. 11 , Nov. 1979, pp.479–484. [PubMed: 388013]
• [ 7 ] Spitz, W.V. and Fisher, R.S., Medicolegal Investigation of Death: Guidelines for the Application of Pathology to Crime Investigation , 2nd ed., Charles C Thomas, Springfield, IL, 1980.
• [ 8 ] Burgon, J., “Carbon Monoxide Poisoning,” Critical Care Update , National Critical Care Institute, Orange, CA, Feb. 1983.
• [ 9 ] Robbins, S.L., Cotran, R.S., and Kumar, V., Pathologic Basis of Disease , W.B.Saunders Co., Philadelphia, 1984.
• [ 10 ] Goldbaum, L.R., “Is Carboxyhemoglobin Concentration the Indicator of Carbon Monoxide Toxicity?” Legal Medicine Annual , C.H.Wecht, editor. , Ed., Appleton-Century Crofts, New York, 1976. [PubMed: 865219]
• [ 11 ] Longo, L.D., “Carbon Monoxide in the Pregnant Mother and Fetus and Its Exchange Across the Placenta,” Annals of the New York Academy of Sciences , Vol. 174,1970, pp.313–341. [PubMed: 4943972]
• [ 12 ] Hill, E.P., Hill, J.R., Power, G.G., and Longo, L.D., “Carbon Monoxide Exchanges Between the Human Fetus and Mother: A Mathematical Model,” American Journal of Phys iology , Vol. 232, No. 3 , 1977, pp. H311–H323. [PubMed: 842687]
• [ 13 ] Longo, L.D. and Hill, E.P., “Carbon Monoxide Uptake and Elimination in Fetal and Maternal Sheep,” American Journal of Physiology , Vol. 232, No. 3 , 1977, pp. H324–H330. [PubMed: 842688]
• [ 14 ] Margulies, J.L., “Acute Carbon Monoxide Poisoning During Pregnancy,” American Journal of Emergency Medicine , Vol. 4,1986, pp.516–519. [PubMed: 3778597]
• [ 15 ] Van Hoesen, K.B., Camporesi, E.M., Moon, R.E., Hage, M.L., and Piantadosi, C.A., “Should Hyperbaric Oxygen Be Used to Treat the Pregnant Patient for Acute Carbon Monoxide Poisoning? A Case Report and Literature Review,” Journal of the American Medical Asso ciation , Vol. 261, No. 7 , 17 Feb. 1989, pp.1039–1043. [PubMed: 2644457]

Case Study

A hazardous waste worker with delayed onset abdominal pain, nausea, vomiting, and diarrhea

As the physician on duty at a hospital emergency department (ED) in an urban community, you are notified that three hazardous waste workers—two men and a woman—are being transported from their worksite by ambulance. All three workers are complaining of headache, dizziness, and nausea.

You learn that the workers were handling several dozen barrels of a sweet-smelling hazardous waste liquid in a hot, unventilated room. Their work required taking samples from barrels, which were obtained from a defunct chlorofluorocarbon manufacturing plant. All three workers were initially wearing full-face respirators and protective clothing, but the younger man removed his respirator early in the day because he had a hangover and was nauseated; he felt it was more convenient to work without being hampered by the respirator. The other two workers continued in full protective gear. After 3 to 4 hours, the three workers began to experience symptoms.

Physical examinations of the workers are conducted in the ED. The older man's and woman's results are normal. Their symptoms subside within 2 hours, and they are discharged.

The younger man, however, has trouble concentrating and is mildly ataxic. His initial blood laboratory data are within normal limits, but he is kept under close observation. You learn from the young man that he is aged 25 and has been in good health with no history of similar problems. Last night, in celebration of his birthday, uncharacteristically he drank 9 to 12 beers, which accounts for his hangover this morning. He also mentions that this morning, while cleaning several wounds sustained in a fight the prior evening, he spilled a can of isopropyl alcohol on his hands and clothes but did not bother to change his clothing.

Six hours later, while still in the ED, the young man becomes acutely ill. He has abdominal pain, nausea, vomiting, and diarrhea. His rectal temperature is now 101°F, pulse 140/min, and he has become disoriented and drowsy. Two days after hospital admission he still has an elevated temperature and abnormal laboratory tests as follows: serum creatinine 2.0 mg/dL (normal 0.7 to 1.5); SGOT or AST 80 U/L (normal 7 to 45); total bilirubin 2.4 mg/dL (normal 0.1 to 1.4); PT 15 seconds (normal 10 to 13). Urinalysis reveals 2⁺ proteinurea, and urine output has decreased despite intravenous hydration.

(a) What is the possible clinical course for this young man?

_________________________________________________________________

(b) How will you identify the material to which the workers have been exposed?

_________________________________________________________________

(c) What treatment or antidote would you consider for the patient?

_________________________________________________________________

Answers to pretest questions may be found on page 15.

Exposure Pathways

❑ In the United States, most industrial CCl ₄ is used in the synthesis of CFCs and chlorinated solvents. Production and usage is declining.

❑ Sources of environmental contamination include industrial and hazardous waste sites.

Carbon tetrachloride (CCl₄) is a clear, nonflammable, heavy liquid that evaporates readily, producing a sweet odor. Although CCl₄ does not occur naturally, it is ubiquitous in the environment. Its chemical stability results in an atmospheric half-life of 30 to 100 years. While CCl₄ does not photodegrade in the ambient air, it may degrade in the presence of the shorter ultraviolet radiation found in the stratosphere. Synonyms for carbon tetrachloride include tetrachloromethane, carbon tet, carbona, tetrasol, and carbon chloride.

Acute CCl₄ toxicity in the workplace was widely recognized by the 1950s. Since then, CCl₄ manufacture and use have decreased. Today, most CCl₄ is consumed in the synthesis of chlorofluorocarbons (CFCs), which are used as heat transfer agents in refrigerating equipment and as aerosol propellents. Because of recent international agreements to restrict the use of CFCs, which are thought to deplete the earth's protective ozone layer, production of CCl₄ will most likely continue to decline. Minor amounts of CCl₄ are still used as an industrial solvent for oils, fats, lacquers, pesticides, varnishes, rubber, waxes, and resins. The largest source of CCl₄ release has been from the fumigation of grains and other substances. In 1986, CCl₄ fumigation was banned except for preserving museum artifacts.

In the United States, CCl₄ has been used widely as an industrial and household cleaning fluid. In industry, it was an effective metal-degreaser, and in the home, it was used to remove spots from clothing, furniture, and carpets. CCl₄ also has been used as an extracting solvent for flowers and seeds, as a component in fire extinguishers, as an anthelmintic and anesthetic, and until 1969, as a waterless shampoo. CCl₄ is still used for many of these purposes in Europe and the third world.

The general population may be exposed to small amounts of CCl₄ through ambient air. Sources producing concentrations that are above background levels include industrial locations where CCl₄ is still used and chemical waste sites where emissions into air, water, or soil are not controlled properly. In 1983, the average atmospheric background level in rural areas was 0.13 parts per billion (ppb); average levels in suburban and urban areas were 0.19 ppb. The Environmental Protection Agency (EPA) has estimated that a lifetime exposure to 0.11 ppb CCl₄ in air causes an excess risk of, at most, one additional cancer in a population of 100,000 people exposed. Before 1988, global atmospheric levels of CCl₄ steadily increased by about 1.3% per year, but they will most likely decline in the future due to decreasing CCl₄ production. Concentrations indoors are often higher than outdoors, indicating that building materials or products such as pesticides and cleaning agents inside the home may be a source of airborne CCl₄.

Because of its moderate solubility in water and its relatively high rate of volatilization from water, only about 1% of the total CCl₄ found in the environment is dissolved in surface waters and oceans. The results of surveys performed by the federal government show that about 99% of all groundwater supplies and about 95% of all surface water supplies contain less than 0.5 ppb of CCl₄. The EPA maximum contaminant level (MCL) for drinking water is 5 ppb.

Who's at Risk

❑ Workers using CCl ₄ or CCl ₄ -containing products are at greatest risk of exposure.

❑ Few cases of CCl ₄ toxicity have occurred since the institution of industrial standards.

❑ Moderate to heavy drinkers and diabetics may be at increased risk of CCl ₄ 's adverse effects.

Workers employed in industries that manufacture or use CCl₄ are at greatest risk of exposure. According to a 1981–1983 survey, about 58,000 workers are exposed to CCl₄ in the United States; however, phase-out of the solvent will most likely decrease the number of exposures. Although inhaled CCl₄ has been associated with liver and kidney damage, exposure at current permissible airborne levels in the workplace is not linked to chronic disease. Workers who may be exposed to CCl₄ include the following:

air transportation workers

automobile mechanics^*

dry cleaners^*

grain workers (inspection, storage, milling, processing)^*

hazardous waste workers

museum workers

pesticide applicators^*

pharmaceutical manufacturers

steel mill and blast furnace workers

telephone and telegraph equipment manufacturers

workers in tin-waste recovery operations

People living near chemical plants where fugitive emissions of CCl₄ occur may be exposed to elevated levels of this chlorocarbon. Other populations at risk of exposure to CCl₄ include people living near chemical waste sites where CCl₄ is improperly stored.

The toxic metabolites of CCl₄ are produced from reactions mediated by mixed function oxidase (MFO) enzymes occurring primarily in the liver and kidneys; therefore, persons with increased MFO enzyme activity may produce toxic CCl₄ metabolites at a faster rate and may be more susceptible to CCl₄-induced effects. These include persons taking certain medications (such as barbiturates), and persons exposed to chlorinated insecticides (such as DDT, chlordecone, or mirex) or halogenated industrial chemicals (such as polychlorinated biphenyls). Triamcinolone and progesterone may also potentiate the effects of relatively moderate CCl₄ exposure.

Alcohols (methanol, ethanol, and isopropyl alcohol) and their ketone analogues are known MFO inducers; hence, persons with a history of moderate or heavy ethanol abuse and those with poorly controlled diabetes may be at increased risk of CCl₄'s harmful effects. Even in nonhabitual drinkers, ethanol intake up to 12 hours before CCl₄ exposure increases risk. Most occupational fatalities due to CCl₄ inhalation involve alcohol abusers; fatal toxicity rarely occurs in nondrinking patients.

Animal studies have demonstrated that fasting or consuming diets low in antioxidants (such as vitamin E, selenium, or methionine) can lead to increased hepatotoxicity from CCl₄ exposure although this effect has not been proven in humans. Persons with preexisting hepatic necrosis or cirrhosis or underlying renal disease appear to have increased susceptibility to CCl₄-induced toxicity and are at increased risk of subsequent liver cancer.

Although CCl₄ is not toxic to the fetus in most animal models, results of studies indicate that the human fetal MFO enzyme system may be operational in the later stages of development and can be induced by certain maternal exposures (e.g., cigarette smoke). Therefore, susceptibility of the human fetus to adverse effects of CCl₄ may depend on developmental stage and on duration and concentration of exposure.

Biologic Fate

❑ CCl ₄ is absorbed readily by all exposure routes.

❑ Evidence indicates that CCl ₄ metabolism occurs via a free-radical intermediate.

❑ Elimination of CCl ₄ occurs in two phases. Some inhaled CCl ₄ is rapidly exhaled unchanged. A small amount of inhaled CCl ₄ temporarily enters fat tissue and later emerges and is excreted.

CCl₄ readily enters the body by inhalation, ingestion, and dermal absorption. Inhalation is the primary route of exposure, with pulmonary absorption in humans estimated to be 60%. The rate of absorption through the gastrointestinal tract is rapid and greatly affected by diet (e.g., fat or alcohol in the gut enhances CCl₄ absorption). CCl₄ also is absorbed through the skin, though less readily than by the lungs. Dermally, the liquid is more rapidly absorbed than the vapor, and prolonged skin contact with the liquid can result in systemic effects.

Few quantitative studies of CCl₄ absorption and distribution in humans have been reported. In experimental animals, CCl₄ is dispersed to all organs and tissues proportionate to blood perfusion and lipid content; the brain has the highest levels after inhalation or oral administration. The rate of inhalation absorption in humans decreases as the duration of exposure or dose increases, indicating a saturable metabolic pathway.

In humans, approximately 50% to 80% of a dose absorbed by the lungs is exhaled unchanged. Some CCl₄ temporarily enters fat tissue. After exposure ceases, CCl₄ continues to emerge from fat and is removed by the lungs. About 4% of all metabolized CCl₄ is converted directly to CO₂ and is exhaled; the remainder forms adducts with proteins and other cellular molecules. The adducts are degraded (half-life about 24 hours) and their products excreted mainly in urine and feces.

Bioactivation of CCl₄ has become the model for chemical toxicity induced by free radicals—a mechanism of toxic injury similar to that associated with radiation and the aging process. The results of studies with experimental animals indicate that the first step in CCl₄ metabolism may involve the formation of a trichloromethyl free radical (•CCl₃) via the cytochrome P-450 enzyme system (Figure 1). The •CCl₃ radical is postulated to bind directly to microsomal lipids and other cellular macromolecules, contributing to the breakdown of membrane structure and disrupting cell energy processes and protein synthesis. The •CCl₃ radical also may undergo anaerobic reactions, resulting in the formation of a variety of toxins including chloroform (CHCl₃), hexachloroethane (Cl₃CCCl₃), and carbon monoxide (CO). In aerobic metabolism, the •CCl₃ radical can yield trichloromethanol (Cl₃COH), a precursor to phosgene (COCl₂), which is then hydrolyzed to form CO₂.

Figure 1.

Products of CCl ₄ metabolism*

Physiologic Effects

The immediate effect of acute CCl₄ exposure by all routes is central nervous system (CNS) depression. If the patient survives this immediate effect, death is usually due to hepatic or renal injury. Adverse effects to other organs are likely to be secondary to CNS, liver, or kidney damage. CCl₄ is classified as a potential human carcinogen based on results of studies that indicate ingested CCl₄ increases the frequency of liver tumors in experimental animals.

Clinical Evaluation

No unique pattern characterizes acute or chronic CCl₄-induced illness. Diagnosis is based on a history of exposure and the clinical signs including CNS depression, dysrhythmias, and hepatic necrosis.

Workplace

Environment

Suggested Reading List

Sources of Information

More information on the adverse effects of carbon tetrachloride and treating and managing cases of exposure to carbon tetrachloride can be obtained from ATSDR, your state and local health departments, and university medical centers. Case Studies in Environmental Medicine: Carbon Tetrachloride Toxicity is one of a series. For other publications in this series, please use the order form on the back cover. For clinical inquiries, contact ATSDR, Division of Health Education, Office of the Director, at (404) 639–6204.

Answers to Pretest and Challenge Questions

Challenge

Challenge questions begin on page 5.

(1)

The older man's history of alcoholism and hepatitis B could put him at increased risk of CCl₄'s adverse effects. Underlying liver damage would increase risk of acute effects and subsequent hepatocellular carcinoma. Although he was working in an appropriate protective suit and full-face respirator, it is unclear whether he has been exposed. His beard may have prevented proper fit of the respirator face piece. However, his symptoms could be due to working in a hot, enclosed space, or they may be psychophysiologic.

(2)

It is not clear that this woman has been exposed to CCl₄. Her symptoms may be morning sickness associated with her pregnancy. However, it is important that she discuss this possible exposure with her obstetrician.

Although CCl₄ is lipophilic and may readily pass through the placenta to the fetus after maternal exposure, CCl₄ does not appear to be teratogenic in either animals or humans in the early stages of pregnancy. The human fetus typically develops the enzyme system necessary for the (toxic) metabolism of CCl₄ in the later months of pregnancy. Although it would be important to know if the mother is exposed to other exogenous MFO-inducing agents, it is doubtful that the 6-week-old fetus has been significantly affected. Nevertheless, it would be prudent to inform the parents and medical-care provider of the possible consequence of in utero exposure.

(3)

Because the young man removed his respirator and presumably breathed the solvent for a prolonged time, he is at high risk. The odor was characterized as sweet smelling, which indicates that the air level was above 10 ppm (the CCl₄ odor threshold). His prior ethanol intake and possibly his concurrent exposure to isopropyl alcohol increase his risk. Alcohols can induce production of MFO enzymes, thereby potentiating the formation of CCl₄ toxic intermediates and metabolites.

(4)

See answer to Pretest question (a).

(5)

Initial actions include removing all contaminated clothing (since dermal absorption of some solvents is high) and cleansing the skin with mild soap and water. Care should be taken to prevent exposure of ED personnel to fumes from contaminated clothing; if possible, the patient should be decontaminated before entering the ED.

The following laboratory work-up is recommended for patients exposed to volatile solvents: baseline hepatic and renal function tests (i.e., SGOT [AST], SGPT [ALT], bilirubin, alkaline phosphatase, BUN, creatinine, electrolytes, and urinalysis), as well as PT, PTT, and CBC. Some solvents may cause dysrhythmias and pulmonary edema (probably secondary to renal toxicity); thus, a baseline electrocardiogram and chest X ray should be obtained. These tests should be repeated periodically to monitor the patient's condition.

You may wish to send blood and urine for a toxic substance screen concentrating on hepatotoxic agents such as acetaminophen and ethanol. If a laboratory is available that performs head space analysis by gas chromatography, a sealed, refrigerated blood sample can be analyzed for volatile solvents. The likelihood of confirming a patient's solvent exposure depends on the dose of solvent received, the time of sampling in relation to the time of exposure, and precautions taken during the collection and storage of the sample. Generally, analysis is most effective if performed within 24 hours after the exposure.

Appropriate public or occupational health reports should be filed. Some states may require that a doctor's first report of illness be filed with the state health department. These reports are often overlooked by ED physicians.

(6)

See answer to Pretest question (c).

(7)

Immediate follow-up for the acutely ill patient consists of monitoring liver and kidney functions for up to 2 weeks. The patient's cardiac and pulmonary systems and clotting ability should also be evaluated periodically since abnormalities can occur secondary to hepatic and renal damage. If the patient shows no improvement, liver biopsy may be considered since liver enzyme levels are not always reliable predictors of liver damage. Liver biopsy is contraindicated in patients with coagulation disorders.

Persons exposed to CCl₄ who have survived without permanent physiologic damage have experienced nausea, dizziness, vision changes, abdominal pain, or delirium up to 24 hours after exposure. The patient's two coworkers, however, may suffer effects because of their unique circumstances. See answers to Challenge questions 1 and 2.

All three persons (the patient and his two coworkers) should be counseled to avoid other hepatotoxic agents such as ethanol, drugs, solvents, and chlorinated compounds. The 40-year-old worker (with possible liver injury as a result of alcoholism and hepatitis B), who was discharged the morning after the incident, and the acutely ill 25-year-old patient may be at increased risk for hepatocellular carcinoma; they should be monitored periodically. It may be advisable for the 25-year-old patient to get the hepatitis B vaccine as a preventive measure. The 30-year-old woman, who used full protective gear and whose symptoms disappeared quickly, is probably at minimal risk. See Challenge question and answer 2.

(8)

It is important that the company establish a protocol for periodic health examinations of all employees. A complete exposure history for each employee should be maintained and made available to the physician. Under the OSHA Hazard Communication regulation (right-to-know provisions), MSDSs for hazardous chemicals in the workplace must be made available to the workers, their physician, and designated worker representative. All employees using a respirator should be fit-tested and all should be properly trained before entering a hazardous environment. Proper supervision is necessary at all times. Employees who are ill should not be allowed to remain at work, nor should employees be permitted to work without the requisite protective gear.

Case Study

A young couple with neurologic symptoms and loss of appetite

You are consulted by a couple in their mid-20s who moved to your southern rural community about 2 years ago and purchased an old farm. They have not felt well since their first winter in the home, when they began to experience general malaise and loss of appetite. They both have had transient nasal congestion and severe headaches that lasted 2 to 3 hours, sometimes accompanied by lightheadedness. These symptoms are especially noticeable after they work in their basement workshop. Once or twice, the wife was nauseated when she returned from the basement after several hours in the workshop.

In a recent conversation with their neighbor, your patients learned that the previous occupants, a young couple, had left the farm convinced that the wife's two miscarriages were due to termite fumigation of the house carried out 3 years before your patients moved in. They ask you if the association is possible, and whether this pesticide may also be the reason that they have not been able to conceive; they have not used birth control for about 1 1/2 years.

On further questioning, you learn that the couple had been well before their move; they exercise regularly and are quite health-conscious. Neither has ever smoked tobacco, and they rarely drink alcohol. It was their desire to start a family and to seek a less stressful life that prompted them to leave their jobs in the city and to attempt organic farming. Further history reveals that the woman's last menstrual period was 5 weeks ago, but her menses have always been irregular. She has had no previous pregnancies.

Physical examinations are generally unrevealing. Complete blood counts, urinalyses, and chemistry profiles are all within normal limits, except for slight elevations of LDH and alkaline phosphatase in the man.

(a) What problem lists would you consider for these patients?

_________________________________________________________________

(b) What further investigations would you consider doing at this time? Where could you obtain assistance in investigating these complaints?

_________________________________________________________________

_________________________________________________________________

(c) What is the likelihood that the miscarriages of the former occupant or the inability of these patients to conceive is related to the termite fumigation? Explain.

_________________________________________________________________

_________________________________________________________________

Answers to the Pretest questions are on page 17.

Exposure Pathways

❑ Chlordane was used for more than 35 years as an termiticide and agricultural insecticide.

Chlordane was the most commonly used member of the cyclodiene family of chlorinated insecticides that includes aldrin, dieldrin, and heptachlor. Depending on the degree of purity, chlordane may vary from a brown liquid to a white, crystalline solid. It has been described as odorless or having a chlorine-like or solvent-like odor. Technical or commercial-grade chlordane is a mixture of two chlordane isomers and more than 100 related reaction products. Chlordane manufactured before 1951 had a higher percentage of impurities than that produced later, which may have been responsible for some of the adverse health effects (especially irritant effects) associated with its earlier use. Trade names of chlordane-containing products include Chlor-Kil^*, Dowchlor, Gold Crest C-100, Octa-Klor, Topiclor 20, and Velsicol 1068.

❑ Indoor air contaminated by misapplication of chlordane is the greatest source of exposure risk for the general population.

From about 1950 until it was banned, chlordane was used widely as a spray to protect structures against termites and to control insects on lawns, turf, ornamental plants, agricultural crops, and in drainage ditches. Subterranean injection of chlordane was also done to control termites. The amount of chlordane applied in the United States in the past 40 years is conservatively estimated at 200 million pounds; each year approximately 1.2 million homes were treated for termites.

❑ Food grown on chlordane-contaminated land and fish from waters contaminated by agricultural runoff are potential sources of chlordane exposure.

Concern about the risk of cancer and slow environmental degradation led the U.S. Environmental Protection Agency (EPA) to prohibit the use of chlordane on food crops in March 1978. Because no effective alternative chemicals were available at the time, chlordane's use for termite control continued until April 1988. Since then, both the sale and use of chlordane in the United States have ceased, and several foreign countries have banned it as well. Nevertheless, an estimated 40 to 75 million pounds of chlordane may still exist unaltered in the environment. Chlordane may be found in food, air, water, and soil, and most people have some form of it in their adipose tissue.

The major source of chlordane exposure today for the general U.S. population is indoor air, a result of the continuing volatilization from prior application in and around homes. Chlordane is usually undetectable in homes properly treated. However, homes treated improperly often have airborne levels of chlordane above the National Academy of Sciences (NAS) safety guideline of 5 micrograms per cubic meter (5 µg/m³) of air. Improper treatment includes pouring the chemical at the foundation line, carelessly injecting liquid chlordane directly into living spaces or air ducts, or spraying excessively in crawl spaces. If overspraying was done, emission of chlordane from joists and flooring can persist for 15 years after treatment. In addition to inhaling volatilized chlordane, persons can receive dermal exposure from contact with contaminated soil near treated houses or from previous lawn, garden, or agricultural application. In soil, chlordane resists chemical and microbial decomposition, remaining biologically active for 30 years or more.

❑ Except in unusual circumstances, chlordane is unlikely to reach and contaminate underground water sources.

Outdoor air contains only minute amounts of chlordane, primarily the result of volatilization from soil and water, as well as from wind erosion. Chlordane is readily degraded by photolysis and hydroxyl radical reactions, resulting in a half-life in outdoor air of about 1.3 days. In the environment, rain fallout and dry deposition are not significant transport mechanisms for chlordane.

Most chlordane water contamination occurs in surface water, the result of industrial releases, urban or rural runoff, or spraying near or over exposed bodies of water. In lakes or streams, chlordane adsorbs almost completely to sediment in about 6 days. Because it is lipophilic and is only slowly metabolized and cleared from the body of many species, it bioaccumulates in aquatic life and has the potential to concentrate in the food chain. Groundwater contamination is not likely to occur because chlordane adsorbs strongly to soils high in clay or organic material. Around waste sites, however, organic solvents can facilitate leaching, thereby allowing chlordane to reach underground aquifers.

Contaminated food is another source of chlordane exposure. Eating fish from chlordane-contaminated waters may add to a person's total body burden. Contaminated fish and other foods are assumed to account for 90% of the body burdens in the populations of Nordic countries where chlordane use was minimal. Certain crops, especially corn, can absorb chlordane from previously treated soil. The daily U.S. intake of chlordane from all sources is estimated to be 0.1 micrograms per kilogram of body weight per day (0.1 µg/kg/day). The World Health Organization (WHO) recommends an upper limit acceptable daily intake (ADI) of 1 µg/kg/day.

Who's at Risk

❑ EPA estimates that 52 million persons are potentially exposed to chlordane in their homes.

Persons with the greatest exposure to chlordane are most likely to be those employed in occupations in which handling the pesticide is common, including manufacture, distribution, and application. Because chlordane is now banned commercially in the United States, the only current occupational exposures would be from chlordane manufactured for export and from chlordane disposal. Chlordane has been found at 166 of 1300 hazardous waste sites on the EPA National Priorities List.

When chlordane was available commercially, most cases of systemic chlordane toxicity occurred after acute dermal exposure or accidental or suicidal ingestion. Today, most people at increased risk of chlordane exposure (primarily via inhalation) are occupants of houses previously treated for termite control. Chlordane was used throughout much of the United States, but most treated structures are located in the South and far West, where termite infestations are a significant problem.

In 1987, EPA estimated that as many as 52 million persons may be exposed to chlordane in their homes. Most homes have been treated properly, and the occupants are unlikely to experience adverse effects. However, it is not known what percentage of homes have been treated improperly; even a small percentage could affect a large number of persons.

❑ Infants may be at increased risk if the mother has had significant chlordane exposure.

Children may have increased exposure risk. A chlordane metabolite, heptachlor epoxide, has been detected in maternal and fetal blood and in amniotic fluid, indicating potential exposure in utero. Chlordane accumulates in breast milk, which may increase the risk for nursing infants of significantly exposed mothers. In several surveys of nursing mothers who had no known exposures, chlordane or its metabolites were found in more than 50% of breast milk samples, but the levels found appeared to have no short-term effects on the infants. Children's diet may contribute to their total body burden of this fat-soluble pesticide because they generally drink more milk and eat more foods that are high in fat content than do adults.

Chlordane is metabolized in the liver, where it leads to enzyme induction of the cytochrome P-450 system. Enzyme induction can accelerate the metabolism of many drugs and hormones, requiring dosage adjustments in chlordane-exposed patients taking these medications.

Biologic Fate

❑ Chlordane is absorbed systemically after ingestion, inhalation, and skin contact.

Chlordane is absorbed well by all exposure routes. It has caused fatalities after ingestion or skin contact. An acute oral dose as low as 25 milligrams/kilogram (mg/kg) has caused death in humans. This is about tenfold lower than the oral LD₅₀ dose reported for experimental animals. (The LD₅₀ is the dose that is fatal to 50% of an experimental animal population; the lower the LD₅₀, the more toxic the agent is.) The lethal dermal dose for humans is not known, but dermal LD₅₀ values in animals are low. Once absorbed, chlordane is distributed rapidly throughout the body. Concentrations of chlordane and its metabolites are highest in adipose tissue, spleen, brain, kidney, liver, and breast milk.

❑ Chlordane and its metabolites are preferentially stored in adipose tissue.

The hepatic metabolism of chlordane, which occurs slowly, has not been studied well in humans. Animal studies show that four metabolic pathways probably exist. The primary metabolites— oxychlordane, nonachlor, heptachlor, and heptachlor epoxide—are more toxic than the parent compound.

❑ Excretion of a chlordane dose may take weeks to months.

Chlordane and its metabolites are preferentially stored in adipose tissues, and concentrations increase as exposure duration increases. Oxychlordane is the major metabolite in most species and can account for up to 90% of the chlordane residues in adipose tissue. In acute or subacute poisoning, the fat-to-serum ratio of chlordane residues can be as much as 100:1.

Chlordane metabolites are excreted mainly in the feces and, to a lesser degree, in the urine. Excretion is slow, taking weeks to months. Breast milk is a major route of excretion in lactating females. The metabolite oxychlordane has been reported in milk samples of women with no known chlordane exposure at concentrations ranging from 2 to 5 µg oxychlordane per liter of whole milk (2 to 5 parts per billion [ppb]). Concentrations of total chlordane residues in breast milk of mothers with chronic inhalation exposure were up to 188 ppb.

Physiologic Effects

❑ Chlordane affects primarily the nervous system and the liver.

Acute or chronic chlordane exposure may affect the neurologic and hepatic systems. Adverse respiratory and gastrointestinal effects from acute chlordane inhalation or skin contact are generally secondary to central nervous system (CNS) effects. Chlordane was often used as a spray, in which case it was dissolved in a petroleum distillate solvent. The solvent itself could produce adverse health effects. Because of experimental animal data, EPA considers chlordane a probable human carcinogen.

Clinical Evaluation

Treatment and Management

Standards and Regulations

On March 6, 1978, registrations for all uses of chlordane on food crops were cancelled. Chlordane use on nonedible plants and its continued use for subterranean termite control were phased out over the following 5 years. In 1987, a negotiated agreement was reached with the primary U.S. chlordane manufacturer, banning the sale, distribution, and use of chlordane, effective April 14, 1988. The U.S. regulations and guidelines pertaining to chlordane in air, water, and food are summarized below. There are no guidelines for chlordane in soil.

Suggested Reading List

ANSWERS TO PRETEST AND CHALLENGE QUESTIONS

Pretest questions are on page 1. Challenge questions begin on page 3.

Sources of Information

More information on treating patients exposed to chlordane can be obtained from ATSDR, the National Pesticide Telecommunications Network (24-hour hotline, [800] 858–7378), your state and local health departments, and university medical centers. Case Studies in Environmental Medicine: Chlordane Toxicity is one of a series. To obtain other publications in this series, please use the order form on the inside back cover. For clinical inquiries, contact ATSDR, Division of Health Education, Office of the Director, at (404) 639–6204.

Chlordane Environmental Fact Sheet

How does chlordane get inside houses?

Vapors can enter houses after proper or Improper application of chlordane and other termiticides.

Proper application: Factors that may contribute to vapors entering the home include cracks in concrete floors and walls, floor drains, sumps, joints, cracks in hollow block walls, and air ducts (heating, cooling, and ventilation ducts).

Improper application: Indoor contamination can arise from careless injection of liquid chlordane directly into the living space of a house, onto interior walls, or into air ducts located in or below the slab. Surface spraying the soil or the wood in a crawl space is illegal in most states. In fact, any indoor surface spraying of chlordane is an improper application.

Plenum construction: In this type of construction, air is circulated without ductwork through the open area below the house. This allows chlordane vapors to be drawn out of the soil and into the air of the house. Many chlordane labels prohibited application to plenum structures.

Once chlordane vapors get inside a house, what happens?

Chlordane vapors tend to persist inside a house. Indoor air monitoring studies conducted in homes treated properly with termiticides indicate that approximately 90% of the homes treated with chlordane have detectable levels of chlordane in the air 1 year after treatment. These studies also show that houses built on slabs (on the surface of the ground) had lower levels than houses with a basement or a crawl space. Basement rooms had the highest levels. Chlordane has also been found in the soil of treated areas 30 years or more after treatment.

Does the existence of chlordane vapors inside a house necessarily affect the occupants' health?

Although human exposure to chlordane in the home may increase certain health risks, most people who are exposed are not likely to develop these health conditions. The individual risk of developing adverse symptoms is low. Health risks depend on the duration of exposure and the concentration of chemical involved.

In humans, exposure to high levels commonly associated with misuse of chlordane has produced symptoms of headaches, dizziness, muscle twitching, weakness, tingling sensations, and nausea. However, these symptoms may also indicate a wide variety of illnesses unrelated to chlordane exposure. EPA also has concerns about long-term damage to the liver and the central nervous system. In addition, experimental animals exposed to chlordane over a lifetime have developed tumors. The long-term effects in humans exposed at levels lower than those likely to occur from misuse are not known.

How does one know if a house was treated with chlordane?

If a house was treated for subterranean termites before 1981, it is likely that chlordane was used. Also, before 1983, chlordane may have been used in the interior to control other household insects such as ants. Although new termiticides have been approved for use since 1981, chlordane was the one most commonly used before that date. If possible, contact the builder or pest control company that treated the home to determine what chemical was used for treatment.

If chlordane was used, how can the indoor air quality be improved?

The following suggestions will minimize occupants' exposure to chlordane and other indoor air pollutants (e.g., radon).

• Increase the circulation of clean air into the house. When weather permits, periodically open windows and doors, and use fans to mix the air. In crawl spaces, clear or add vents and install a fan to constantly vent crawl-space air to the outside.
• Seal areas that directly come in contact with treated soil, using grout, caulk, or sealant. Fill cracks in basement and ground floors and walls, joints between floors and walls, and openings around pipes, drains, and sumps. Periodically check these areas for signs of new cracks or broken seals because houses settle over time.
• Install a system that supplies outside air to appliances like clothes dryers and furnaces or fireplaces that normally draw air from inside the house. These may actually create a negative pressure within the house and help draw chlordane vapors from the soil into the house through walls, floors, and basements.
• Check the condition of ducts in the crawl space or basement. Use duct tape to seal openings and joints.

If chlordane misapplication is suspected, what can be done?

If improper application of chlordane is suspected, the suggestions above should be followed to improve the indoor air quality. In addition, the air in the home should be tested. Indications of misapplication may include the following:

• the presence of odors inside the house
• an increase in such odors when the heating or cooling system is operating
• evidence of a potential chlordane spill, such as stains, in the house
• similar symptoms in several household occupants

How can a house be tested?

It is important to ensure that the results of air testing are reliable by having qualified laboratory personnel collect and analyze air samples. A laboratory proficient in both indoor air sampling and pesticide analysis should be used. This type of service is generally available only from commercial laboratories. Costs vary according to the amount of testing, but could range from about $50 to $500. To locate a laboratory in the area, you can call the National Pesticide Telecommunications Network (NPTN) at (800) 858–7378 or contact your state or local health department.

How does a person interpret the test results?

In 1982, the National Academy of Sciences published interim guidelines for airborne levels of a number of termiticides. The recommended safe level for chlordane is 5 µg/m³. This guideline is not a critical cut-off point, however. The conditions under which the air sampling was performed will influence the test results. Levels will be higher if the house was closed prior to sampling and if the heat was on, but lower if the humidity is high. A qualified professional should be consulted before abatement or other remedial procedures are undertaken to reduce indoor levels.

What additional steps can be taken to reduce exposure?

If the above suggestions for improving indoor air quality have been followed, the air in the house has been tested, and the air sample results are high, structural modifications may be useful to further reduce the level of chlordane. For homes that were treated properly, modifications are probably not worth the high expense. Modifications must be designed on a case-by-case basis, but may include replacing or relocating air ducts, replacing furnaces or ventilation systems with air exchangers, using barrier coatings of polyvinylidene chloride (e.g., Saranex) or polyamide (e.g., Capran-C), or sealing crawl-space soil with a layer of concrete. Decontamination measures or other mitigation methods should not be undertaken without professional advice.

How can one dispose of unwanted chlordane?

Chlordane can be a serious hazard to the environment as well as to human health. It is illegal to dump chlordane into sinks, toilets, storm drains, or any body of water. Any unused pesticide or its container must be disposed of according to both the instructions on the label and state laws. For clarification of label directions or additional guidance, call NPTN or contact your state pesticide or environmental control agency or a hazardous waste representative at the nearest EPA regional office.

Are any alternatives to chlordane available?

As of July 1987, two alternative termiticides, chlorpyrifos (e.g., Dursban) and permethrin (i.e., Torpedo and Dragnet) were registered with EPA and are available commercially. Chlorpyrifos is an organophosphate pesticide (see Case Studies in Environmental Medicine: Cholinesterase-Inhibiting Pesticide Toxicity ), and permethrin is a synthetic pyrethroid pesticide. EPA has concluded that these termiticides, when used according to label directions, do not pose unreasonable risks.

How can I get more information?

Call the NPTN 24-hour hotline at (800) 858–7378.

CASE REPORT

A 25-year-old man came to the Hahnemann University Hospital Emergency Room with severe dyspnea. He had a history of mild childhood asthma, which had resolved at the age of 5 years. Four years prior to admission, the patient was exposed to a chlorine gas leak while working for a regional sewerage authority. The patient had worked for 2 h in a chlorine-filled enclosed environment without a protective respirator mask. Immediately following this exposure, the patient experienced a transient episode of hemoptysis followed by acute shortness of breath and wheezing. A regimen of aminophylline and inhaled beta-agonists was started in a local emergency room, which resulted in some improvement in his symptoms. His course over the next 4 years was notable for frequent hospitalizations for asthma and increasing use of oral and inhaled corticosteroids. He was admitted to Hahnemann University Hospital for management of an acute exacerbation of his illness and a diagnostic workup.

Physical examination revealed an afebrile, cushingoid patient in moderate respiratory distress. Auscultation of the chest revealed diffuse expiratory wheezes in all lung fields with prolonged expiration.

An arterial blood gas evaluation on room air revealed a pH of 7.45, a Pco₂ of 32.2, and a Po₂ of 73.6. The eosinophil count was 8 cu mm; the immunoglobulin G activity was markedly elevated at 431 U/ml (normal, <122 U/ml). A chest roentgenogram was normal except for minimal peribronchial thickening. An esophagram demonstrated minimal gastroesophageal reflux without aspiration. An Aspergillus skin test was negative. A flow volume loop and otorhinolaryngologic evaluation showed no evidence of upper airway obstruction. Pulmonary function testing revealed an FVC of 2.71 (52 percent of the predicted value [PV]), an FEV₁ of 1.42 (35 percent of PV), an FEV₁/FVC of 52 percent, an FRC of 5.09 (154 percent of PV), and a TLC of 7.43 (107 percent of PV)—values consistent with severe obstruction (normal values from Crapo et al¹ ). Administration of aerosolized albuterol produced a 54 percent improvement in FEV₁ and a 26 percent improvement in FVC, which was reproduced in multiple studies. The single breath diffusion capacity for carbon monoxide was 31.95 (89 percent).

Intravenous methylprednisolone, intravenous aminophylline, and aerosolized terbutaline were given with significant improvement in the patients symptoms and flow rates, although moderate obstruction remained. After several days, the patient was discharged on a regimen of high-dose oral corticosteroids with persistent airflow obstruction.

DISCUSSION

Although today most reported cases of chlorine exposure occur in industrial settings,^2,3 at water treatment facilities,⁴ or as a result of transportation accidents,^5,6 several cases of toxic chlorine inhalation have occurred in more unusual circumstances. An increasingly common source of exposure to chlorine gas is fumes liberated from chlorine products used in residential pools and spas.^7,8 Cases of exposure resulting from chlorine gas released during mixing of a variety of household cleaning agents⁹ have prompted the placement of consumer warnings on many such products. One episode of voluntary exposure has also been reported.¹⁰

The long-term pulmonary sequelae of chlorine gas inhalation are controversial. Studies of soldiers gassed during the First World War showed evidence of obstructive airway disease and permanent disability.^6,11 It is difficult to ascribe abnormalities found in these patients solely to chlorine inhalation for two reasons: chlorine was used only for a short time in chemical warfare, and most subjects studied were exposed to multiple war gases.¹² More recent series describe an initial obstructive defect, often with partial reversibility^3,13,14; restrictive defects with accompanying diffusion abnormalities have also been reported.^7,14 These initial changes reverted to normal within a few months in almost all patients studied. In fact, in a study involving 820 patients, Jones¹⁵ found no radiologic or clinical evidence of permanent pulmonary damage following industrial chloride exposure. Lawson¹⁶ also found no long-term residual changes in laboratory parameters, chest roentgenographic findings, or pulmonary function test results in over 457 cases of acute industrial chlorine gas exposure. In contrast, Kaufman and Burkons¹² found persistent obstructive lung disease up to 14 months following chronic chlorine exposure, and Kowitz et al⁵ found persistent residual restrictive disease and low diffusing capacities up to 3 years following acute chlorine exposure. In another study, Jones et al⁶ found that long-term sequelae after acute chlorine gas exposure were affected more by cigarette smoking than by the chlorine gas exposure. Other authors¹⁷ have suggested that preexisting lung conditions do not affect the occurrence of pulmonary sequelae following chlorine gas exposure.

Our patient was exposed to chlorine gas in an industrial setting. Although the patient had a history of cigarette smoking and childhood asthma, he had had no symptoms of reactive airways disease for 20 years prior to this event. Following the chlorine exposure, the patients symptoms rapidly became severely debilitating, necessitating daily therapy with high-dose corticosteroids, frequent use of home oxygen, and self-administered subcutaneous epinephrine.

To our knowledge, this case is unique in the literature. Charan et al³ showed reversible acute airway obstruction shortly after exposure, and Hasan et al¹³ reported the cases of two asthmatic patients in whom chlorine gas may have exacerbated a state of underlying hyperactivity. No one, however, has reported new onset of severe reversible airway obstruction that persisted several years after chlorine gas exposure. Thus, we believe that our patient represents a unique case of persistently debilitating asthma following acute chlorine gas exposure.

ACKNOWLEDGMENT: Editorial services were provided by Bette R.Haitsch. The authors would like to thank Angela K.Dorman for her assistance in manuscript preparation.

REFERENCES

1.

Crapo RO, Morris AH, Gardner RM. Reference spirometric values using techniques and equipment that meets ATS recommendations. Am Rev Respir Dis 1981; 123:659. [PubMed: 7271065]

2.

Beach FXM, Jones ES, Scarrow GD. Respiratory effects of chlorine gas. Br J Ind Med 1969; 26:231–36. [PMC free article: PMC1008943] [PubMed: 5794948]

3.

Charan NB, Lakshminarayan S, Myers GC, Smith DD. Effects of accidental chlorine inhalation on pulmonary function. West J Med 1985; 143:333–36. [PMC free article: PMC1306316] [PubMed: 4049853]

4.

Fleta J, CalvoC, Zuniga J, Castellano M, Bueno M. Intoxication of 76 children by chlorine gas. Hum Toxicol 1986; 5:99–100. [PubMed: 3957357]

5.

Kowitz TA, Reba RC, Parker RT, et al. Effects of chlorine gas upon respiratory function. Arch Environ Health 1967; 14:545– 58. [PubMed: 6024479]

6.

Jones RN, Hughes JM, Glindmeyer H, Weill H. Lung function after acute chlorine exposure. Am Rev Respir Dis 1986; 134: 1190–95. [PubMed: 3789518]

7.

Ploysongsang Y, Beach BC, DiLisio RE. Pulmonary function changes after acute inhalation of chlorine gas. South Med J 1982; 75:23–26. [PubMed: 7054876]

8.

Mustchin CP, Pickering CAC. “Coughing water”: bronchial hyperactivity induced by swimming in a chlorinated pool. Thorax 1979; 34:682–83. [PMC free article: PMC471149] [PubMed: 515992]

9.

Murphy DMF, Fairman RP, Lapp NL, Morgan KC. Severe airway disease due to inhalation of fumes from cleansing agents. Chest 1976; 69:372–76. [PubMed: 971606]

1.

Rafferty P. Voluntary chlorine inhalation: a new form of self-abuse? Br Med J 1980; 281:1178–79. [PMC free article: PMC1714479] [PubMed: 6775759]

1.

Sandall TE. The later effects of gas poisoning. Lancet 1922; 2:857.

1.

Kaufman J, Burkons D. Clinical, roentgenologic and physiologic effects of acute chlorine exposure. Arch Environ Health 1971; 23:29–34. [PubMed: 5581256]

1.

Hasan FM, Gehshan A, Fuleihan FJD. Resolution of pulmonary dysfunction following acute chlorine exposure. Arch Environ Health 1983; 38:76–80. [PubMed: 6847255]

1.

Colardyn F, Van Der Straten M, Tasson J, Van Egmond J. Acute chlorine gas intoxication. Acta Clin Belg 1976; 31:70–77. [PubMed: 952180]

1.

Jones AT. Noxious gas and fumes. Proc R Soc Med 1952; 45:609. [PubMed: 13003957]

1.

Lawson JJ. Chlorine exposure: a challenge to the physician. Am Fam Physician 1981; 23:135–38. [PubMed: 7457311]

1.

Barret L, Faure J. Chlorine poisoning, letter. Lancet 1984; 1:561–62. [PubMed: 6142270]

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.

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).

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

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).

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.

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 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).

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.

Clinical Evaluation

Treatment and Management

Standards and Regulations

Table 1 summarizes the U.S. standards and regulations for chromium salts, which are discussed in more detail below.

Table 1.

Standards and regulations for chromium.

Suggested Reading List

Answers to Pretest and Challenge Questions

Challenge

Challenge questions begin on page 4.

(1)

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.

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.

(2)

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.

(3)

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.

(4)

Yes, persistent dermal ulcers, respiratory tract irritation, and pulmonary sensitization are all possible effects of chromium exposure.

(5)

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.

(6)

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.

(7)

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.

(8)

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.

Case Study

Hypotension and coma in a 5-year-old victim of smoke inhalation

You are alerted by paramedics who are en route to the emergency department. They will arrive within 10 minutes with two apparent smoke-inhalation victims: a young woman, approximate age 35, and her son, approximate age 5. Upon arrival at the scene, firefighters found both victims unconscious near the doorway; the entire house was smoke-filled. The fire, which was confined to the child's bedroom and two adjacent rooms, was started by a toy that the child poked into an electric space heater. It is probable that the woman was in another part of the house when the fire began and attempted to rescue the child but was overcome by the thick black smoke. Both victims are unconscious. The paramedics report no evidence of trauma or burns in either victim. The mother has nonpurposeful movements, but the child is flaccid and unresponsive to painful stimuli. Soot is present in the child's nose and throat.

En route to the hospital, IVs were started. The woman's vital signs include BP 70/50 mm Hg, pulse 120/min, respiration rate 30/min. She is being administered 100% oxygen via face mask. The child's vital signs include BP 50/20 mm Hg, pulse 50/min, respiration rate 0/min. He is intubated and mechanically ventilated, and is being administered supplemental oxygen.

Upon arrival at the hospital, the woman is improved but is lethargic and disoriented; the child is still unresponsive even to deep pain. Both victims have adequate pO₂ levels. The mother's initial carboxyhemoglobin level is 25%; the child's carboxyhemoglobin level is 40%. The child remains bradycardic and hypotensive.

The following day, having heard that cyanide may have played a role in the condition of these smoke-inhalation victims, a neighboring couple, who have recently learned that for 2 years they had been drinking well water containing 212 parts per billion (ppb) cyanide, are concerned that they may experience adverse health effects. They ask to be evaluated.

(a) What are the possible causes of coma in the fire victims?

_________________________________________________________________

(b) What laboratory tests would help to confirm the diagnosis?

_________________________________________________________________

(c) What treatment should be initiated immediately?

_________________________________________________________________

(d) What are the possible long-term sequelae for the fire victims and the neighbors who drank cyanide-containing well water?

_________________________________________________________________

Answers can be found in Challenge answers (6) through (13) on pages 18–19.

Exposure Pathways

❑ Many fruits and vegetables contain cyanide-generating substances.

❑ Cyanide contamination in air and water arises primarily from industrial pollution and vehicle exhaust.

❑ Cigarette smoke contains cyanide.

❑ Cyanide poisoning is an inhalation hazard in many enclosed-space fires.

Cyanide is one of the most rapidly acting poisons known and accounts for many suicidal and homicidal deaths. Cyanide can exist in many forms. The most common are hydrogen cyanide (HCN) and cyanide salts (potassium cyanide, sodium cyanide, calcium cyanide), which can combine with acid to release HCN. A number of aliphatic nitrile compounds (i.e., acrylonitrile, acetonitrile, proprionitrile) and aliphatic thiocyanates can release cyanide by hepatic metabolism after absorption, resulting in delayed-onset cyanide poisoning. Children have developed symptoms of cyanide poisoning hours after drinking acetonitrile-based artificial nail remover.

Cyanide salts are generally colorless solids, whereas HCN, also known as prussic acid, is a colorless gas at room temperature. Because of its rapid action, HCN is employed in gas chamber executions in the United States and other countries. A cyanide salt was used in the Jonestown massacre, and potassium cyanide was responsible for the deaths of seven persons in the Chicago area who consumed intentionally tainted capsules of an over-the-counter pain reliever.

Cyanide compounds have a faint, bitter almond odor, detectable at a threshold of 0.2 to 5.0 parts per million (ppm). (The current permissible workplace short-term exposure limit [STEL] for hydrogen cyanide is 10 ppm.) The ability to smell cyanide is a genetically determined trait, which is absent in 20% to 40% of the population.

Cyanogenic glycosides, which occur naturally in a number of plants, release HCN after ingestion. In the United States, cyanide intake through food consumption is normally low since foods high in cyanogenic substances are not a major part of the American diet. However, eating large amounts of seeds, pits, and stone fruits of certain plants (or blending them in “milkshakes”) reportedly has caused illness especially in children, and even death. As many as 1000 plants contain cyanogenic glycosides. The more common include the following:

apple (seeds)

bamboo (sprouts)

cassava (beans and roots)

Christmas berry

crab apple (seeds)

cycad nut

elderberry (leaves and shoots)

hydrangea (leaves and buds)

lima beans (black bean grown in tropical countries)

pear (seeds)

Prunus species (leaves, bark, seeds)

apricot

bitter almond

cherry laurel

chokecherry

mountain mahogany

peach

pin cherry

plum

western chokeberry

wild black cherry

Adapted from Kingsbury JM. Poisonous Plants of the United States and Canada. Englewood Cliffs, NJ: Prentice-Hall, 1964, p 26. Used by permission of Prentice-Hall.

Laetrile, a compound used for cancer treatment by some nontraditional practitioners, contains amygdalin, which releases cyanide when administered orally. Laetrile has been sanctioned in 22 states, despite lack of Federal Drug Administration (FDA) approval. No evidence of laetrile's efficacy exists, and several cases of serious and fatal cyanide poisonings have been reported. Sodium nitroprusside, NaFe(CN)₅NO, is an intravenous medication used in acute hypertensive crises. Its cyanide metabolite can reach toxic levels if the recommended dosage is exceeded, if infusion is prolonged or rapid, or if renal failure occurs. Phencyclidine (PCP), an illicit street drug, may contain cyanide if improperly manufactured.

For the general population, the single largest source of airborne cyanide exposure is vehicle exhaust. Vehicle emission rates can be reduced from 14 milligrams (mg) cyanide per mile to about 1 mg per mile by catalytic converters operating optimally. Other atmospheric sources include emissions from chemical processing industries, iron and steel mills, metallurgical industries, metal plating and finishing industries, petroleum refineries, municipal waste incinerators, and cigarette smoke.

Water sources can be contaminated with cyanide by industrial effluents, migration of cyanide from landfills, and to a lesser extent, by runoff from cyanide-containing salts used on roads. The largest sources of cyanide in water are discharges from organic chemical industries, iron and steel plants, and wastewater treatment works. A 1978 U.S. Environmental Protection Agency (EPA) survey of interstate drinking water supplies showed that about 7% of the samples had cyanide concentrations greater than 10 parts per billion (ppb). (The anticipated drinking water standard to be proposed by EPA in 1990 is 200 ppb.) Cyanide has been detected in some surface waters at concentrations above the level safe for aquatic life.

Virtually any substance containing both carbon and nitrogen can release cyanide when burned under certain conditions. HCN is released during pyrolysis of synthetic polymers containing nitrocellulose, acrylonitrile, or urea formaldehyde. Many common textiles, foam, and plastic materials in the home may be sources of HCN in a fire. Some natural products such as silk and wool can also release cyanide when burned.

Who's at Risk

❑ Workers have the greatest likelihood of exposure to high concentrations of cyanide.

❑ One lighted cigarette can produce 20 to 450 µg of cyanide, increasing the risk to smokers.

❑ The incidence of cyanide poisoning may be underestimated in smoke-inhalation victims.

A 1981–1983 National Institute for Occupational Safety and Health (NIOSH) survey estimated that 143,720 workers in a wide variety of occupations were potentially exposed to cyanide compounds, including, but not limited to, the following:

blacksmiths

chemical laboratory workers

electroplaters

fumigant applicators

manufacturers and users of plastics and paint (acrylates, methacrylates, nitriles)

metallurgists

metal cleaners

photoengravers

reclaimers of silver from photographic materials

steel manufacturers

tanners

Firefighters may be exposed to HCN generated during combustion of certain types of plastics, foams, and textiles. Effects due to occupational exposures are usually the result of inhalation.

Each pack of cigarettes smoked releases 250 to 10,000 micrograms (µg) of cyanide, much of which the smoker may inhale. Smokers generally have higher blood cyanide levels than nonsmokers and are at increased risk of cyanide's nervous system effects, particularly tobacco amblyopia and retrobulbar optic neuritis.

Significant blood cyanide levels have been reported in many fire-related smoke-inhalation victims. In one study of 52 fire fatalities, some victims had very high cyanide levels with relatively low carbon monoxide levels. Data suggest that the risk of cyanide intoxication in enclosed-space smoke inhalation injury is probably underestimated. HCN in the air can cause weakness and loss of muscle coordination, making escape from the area of a fire more difficult.

Biologic Fate

❑ Cyanide is absorbed by all routes.

❑ Cyanide causes cellular asphyxiation by inhibiting the cytochrome oxidase system.

Cyanide is absorbed through the lungs, GI tract, and skin. Symptoms can occur within seconds of HCN inhalation, within minutes after ingestion of cyanide salts, and onset may be delayed up to 12 hours after ingestion of cyanogenic glycosides, nitriles, or thiocyanates. Absorption time after ingestion depends on gut pH and solubility of the cyanide-containing compound. Cyanide is readily absorbed via the mucous membranes and eyes. Clinical cases of cyanide poisoning after dermal exposure are rare and most often have involved burns with molten cyanide salts or immersion in cyanide solutions.

Once cyanide is absorbed, it is rapidly distributed by the blood throughout the body. Cyanide exerts toxic effects by combining with the ferric (+3) iron in cytochrome oxidase, which inhibits cellular oxygen utilization. Blockade of the cytochrome oxidase system causes anaerobic metabolism with resultant lactate production and severe metabolic acidosis. Cyanide also inhibits other enzymes and can combine with certain metabolic intermediates.

Eighty percent of absorbed cyanide is detoxified in the liver by the mitochondrial enzyme rhodanese, which catalyzes the transfer of sulfur from a sulfate donor to cyanide, forming less toxicthiocyanate. Thiocyanate is readily excreted in urine. Other detoxification pathways exist, including reaction with hydroxocobalamin (vitamin B_12a) to form cyanocobalamin. A small amount of cyanide is eliminated as CO₂ in expired air, along with small amounts of HCN.

A number of compounds have been found to act synergistically with cyanide, producing toxic effects. Smoke-inhalation victims have experienced additive or synergistic effects from carbon monoxide and cyanide, and only recently has attention been focused on the potential for combined poisoning in victims of enclosed-space fires.

Physiologic Effects

❑ The cardiovascular, respiratory, central nervous, and endocrine systems may be adversely affected in cyanide poisoning.

Cyanide adversely affects the cardiovascular, respiratory, central nervous, and endocrine systems. It is unlikely that cyanides are carcinogenic. Epidemiologic studies indicate that cyanide may be teratogenic in humans, but data are scarce. Reproductive effects of cyanide in humans have not been studied.

There is great variability among “lethal doses” reported in the literature, probably due to differences in supportive care and therapy rendered. The potential lethal oral adult dose of cyanide salts in the absence of medical care is 200 to 300 mg, although persons ingesting 1 to 3 grams (g) of cyanide salts have survived. Inhaling 600 to 700 ppm hydrogen cyanide for 5 minutes or approximately 200 ppm for 30 minutes may be fatal. Survival in any specific case often depends upon the rapidity and scope of treatment.

Clinical Evaluation

Treatment and Management

Standards and Regulations

A summary of standards and regulations is listed in Table 1.

Table 1.

Standards and regulations for cyanide.

Suggested Reading List

Answers to Pretest and Challenge Questions

Pretest questions are on page 1. Challenge questions begin on page 4.

(1)

Many smoke-inhalation victims are poisoned by both carbon monoxide (elevated carboxyhemoglobin levels) and HCN. HCN is formed during pyrolysis of synthetic and natural materials containing nitrogen. The child placed a toy through the heater grill, it ignited, and the fire spread to carpets, drapes, furniture, wire insulation, etc. Under the right conditions, these items could produce HCN, as well as other noxious gases.

(2)

The known source of cyanide for the neighbors is contaminated drinking water. Other possible sources include cyanogenic foods; vehicle exhaust, active or passive cigarette smoke, and the fire described in the case study. Information to gather would include other residences, diet, smoking history, occupation, hobbies, and other illnesses.

(3)

The two victims would not necessarily have similar blood cyanide levels, even though they were victims of the same fire. The blood cyanide level is a function of the amount and composition of the smoke inhaled. If the mother was in another part of the house and remained unaware of the fire until it had spread, she probably would not have inhaled as much HCN as the child, who was near the fire source. The mother likely received exposure to a lower concentration of smoke and for a shorter duration than the child did.

(4)

Causes of an elevated blood cyanide level might include occupational exposure, heavy cigarette smoking, ingestion of large quantities of cyanogenic plants, nitroprusside therapy, smoke inhalation, or a possible laboratory error. The physician should also consider a suicide or homicide attempt using cyanide salts.

(5)

Assuming vital signs have been adequately maintained and the patients were well supported, the prognosis is generally good unless significant hypoxia, hypotension, or acidosis occurred before treatment and caused end-organ damage. Survival after 4 hours usually indicates recovery. A delayed Parkinsonian syndrome can occur after cyanide poisoning, as well as after carbon monoxide poisoning.

(6)

The blockage of cellular respiration by cyanide prevents extraction and utilization of the oxygen carried in the arteries. As a result, the presence of unused oxygen will raise the oxygen partial pressure and percent O₂ saturation of the venous blood.

(7)

Causes of coma may be grouped as toxicologic or nontoxicologic. Toxicologic causes include carbon monoxide poisoning, cyanide poisoning, or drug overdose. Drug overdose could have resulted in unconsciousness before the fire started. Hypoxemia resulting from any of the above causes may also contribute to continuing coma. Nontoxicologic causes include trauma, particularly to the head, occurring before the fire or to a victim trying to escape the fire.

(8)

One of the initial diagnostic signs of cyanide poisoning in a smoke-inhalation victim is the absence of cyanosis despite respiratory depression. The persistence of acidosis and continued bradycardia and hypotension also suggest cyanide poisoning, and antidote should be administered.

(9)

A whole blood cyanide level of greater than 1.0 µg/mL is diagnostic of significant cyanide exposure. The laboratory requires 4 to 6 hours to perform this test, however, so it is useful only for confirmation or documentation of the diagnosis and cannot be used to guide emergency management.

An elevated carboxyhemoglobin level (greater than 30%) in a smoke-inhalation victim should provoke suspicion of a concomitant cyanide poisoning. Persistent metabolic acidosis after hypotension has been alleviated, which is consistent with cyanide intoxication, can be determined from the pH or CO₂ content. An valuable clue. However, because respiratory depression or pulmonary damage are likely to occur in such patients, and because inspired oxygen concentrations may vary, a normal venous or mixed venous pO₂ level in a given setting may be unknown.

(10)

For smoke-inhalation victims, 100% oxygen should be administered immediately and IV access established.

(11)

The biologic half-life of carbon monoxide using 100% oxygen is 60 to 90 minutes. If hypotension, bradycardia, or acidosis persist, cyanide poisoning is likely, and antidote should be administered. Methemoglobin levels should be monitored carefully throughout nitrite therapy. Blood pressure also should be monitored and the nitrite infusion rate slowed if hypotension occurs.

(12)

The two major side effects of sodium nitrite from the antidote kit are excessive methemoglobinemia and hypotension. Methemoglobinemia is due to the oxidation of ferrous (+2) iron in hemoglobin to ferric (+3) by nitrite, and, therefore, care must be taken to avoid excessive nitrite doses. Hypotension results from the vasodilating action of nitrite.

(13)

Short-term sequelae of patients acutely poisoned by cyanide may include tremors and convulsions. Longer-term effects may include posthypoxic brain damage and myocardial lesions.

The long-term sequelae in persons chronically exposed to cyanide depend on exposure level and duration. In occupational settings, mild abnormalities in vitamin B₁₂, folate, TSH levels, and thyroid function have been reported. Enlarged thyroid, dyspnea on exertion, psychosis, encephalopathy, and myocardial lesions have also been noted but may be due to multiple episodes of subacute poisoning rather than true chronic exposure. In populations consuming large quantities of cassava, endemic goiter, neuropathies, and cretinism have been noted, although dietary deficiencies may have contributed to these effects. Retrobulbar optic neuritis in heavy smokers has also been linked to chronic, low-level cyanide exposure from cigarette smoke.

Whether the neighbors described in the case study who have had chronic cyanide exposure through drinking water will experience long-term effects is difficult to predict. The level of cyanide in their drinking water (212 ppb) is close to what the EPA will propose in 1990 (200 ppb). The amount of cyanide ingested through cassava consumption in the Mozambique population is unknown, and comparisons are not warranted. Persons chronically exposed to low levels of cyanide have not been adequately studied. However, if neurologic, ophthalmologic, and thyroid examinations are normal, reassurance should be given that no ill effects from consumption of the water are evident. The local or state health department could be consulted to obtain assistance with possible control measures to remove cyanide from the well water.

Sources of Information

More information on the adverse effects of cyanide and the treatment and management of cyanide-exposed persons can be obtained from ATSDR, your state and local health departments, and university medical centers. Case Studies in Environmental Medicine: Cyanide Toxicity is one of a series. For other publications in this series, please use the order form on the back cover. For clinical inquiries, contact ATSDR, Division of Health Education, Office of Director, at (404) 639–6204.

Case Study

A 5-year-old boy with a vesicular facial rash one day after contact with an herbicide

A 5-year-old boy is brought to your office after acute onset of a rash on his face and arms. The rash consists of small blisters with surrounding erythema, which the patient states itch and burn. The boy's mother says she noticed the rash on her son's face last evening, and by morning it had spread to both arms. The child also complains of a headache and stomachache that began early this morning. His temperature is normal.

Further history reveals that the patient and his family moved to this Midwest rural area 2 years ago; their farm is adjacent to a wooded area. Two days ago, workmen from a utility company sprayed beneath the high-voltage power lines that traverse the back edge of the property where the children frequently play during the summer. On questioning, the workmen told the mother they were using an herbicide, but assured her the area would be safe for the children in a few hours. The mother asks you if the defoliant could have contained dioxins, and, if so, whether her child has been affected. Her concern stems from what she has heard about alleged effects of Agent Orange on Vietnam veterans.

Medical history and chart review reveal the child has had no major illnesses. He has had a normal pattern of growth and development, both physical and psychosocial. Immunizations are up to date.

(a) What further questions would you ask while taking the medical history?

_________________________________________________________________

(b) On what aspect of the boy's physical examination should you focus to address the mother's concern?

_________________________________________________________________

(c) What laboratory tests are appropriate to aid in the diagnosis?

_________________________________________________________________

(d) Are dioxins likely to be the cause of the boy's rash? Explain.

_________________________________________________________________

Answers to the Pretest are incorporated in Challenge answers (6) through (10) on page 16.

Exposure Pathways

❑ The general population's principal route of dioxin exposure is through the food chain.

❑ Other minor dioxin sources are diesel exhaust, chlorine-bleached paper products, and incineration gases.

Dioxins and furans are terms applied to polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (Figure 1). They are believed to produce similar health effects and are known to coexist as unwanted contaminants in various materials. Because 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is the most thoroughly studied and most toxic of the 75 dioxin isomers, the term TCDD is used interchangeably with dioxins throughout this monograph. As a pure solid, TCDD is colorless, odorless, lipid-soluble, and only sparingly soluble in water.

Figure 1.

Chemical structure of dioxins and related compounds

Dioxins, as well as furans, have received much media attention in the past few decades and hence have become a public concern. Dioxins' reputation as extremely toxic is based primarily on tests performed on guinea pigs, the most dioxin-sensitive mammalian species. By comparison, the hamster is 5000 to 10,000 times more resistant in similar toxicity tests. Extrapolation to humans from data based on animal studies is difficult because species vary widely in their sensitivity to dioxins and human risk assessment models are uncertain.

Several human populations exposed to dioxin-contaminated compounds have been studied extensively for health effects. Some Vietnam veterans were potentially exposed to dioxins through the military use of the defoliant Agent Orange (a mixture of 2,4,5-trichlorophenoxyacetic acid [2,4,5-T] and 2,4-dichlorophenoxyacetic acid [2,4-D] contaminated with TCDD). Several areas of the United States have been contaminated as a result of industrial discharges or spraying of dirt roads with dioxin-contaminated waste oils. Three areas that have received notoriety are Love Canal in Niagara Falls, New York; Times Beach, Missouri; and Newark, New Jersey. The most highly publicized accident affecting a residential population was an explosion at a chemical plant that resulted in an airborne discharge of dioxins over Seveso, Italy, in 1976. More than 37,000 people lived in an area that may have been contaminated by dioxins. In all cases, there were no deaths from acute poisoning, and concomitant exposure to other toxic substances may have contributed to the effects that were observed.

Dioxins are formed during the production of many chlorinated organic solvents, hexachlorophene, and the herbicide 2,4,5-T. Emissions from coal-burning power plants, exhaust from diesel engines, and the incomplete burning of wastes containing chlorine, such as PVC plastic form both dioxins and furans; they are also naturally produced in small amounts by volcanoes and forest fires. In nature, dioxins are found adsorbed on air and soil particles. TCDD concentrations in water and on vegetation are generally below present detection limits.

Extremely small quantities of dioxins are found nearly everywhere in the developed world. Minute amounts of TCDD have been detected in paper pulp, formed when chlorine is added during the bleaching process. TCDD reportedly has been leached from milk cartons and from coffee filters (less than 50 parts per trillion [ppt]). The amount of dioxins detected in paper-based personal care products such as disposable diapers, facial or toilet tissue, and paper towels is considered insignificant.

Because dioxins bioaccumulate in the food chain, the major route of human exposure is through food, especially fish, meat, and dairy products. It has been estimated that food accounts for 98% of total adult exposures. TCDD has been detected in fish from Saginaw Bay, contaminated sections of the Great Lakes, and some Michigan rivers, although levels in both the water and fish have decreased over time.

Use of products known or thought to be contaminated by dioxins and furans has been significantly restricted in the last few decades. The U.S. Environmental Protection Agency (EPA) has removed the herbicide 2,4,5-T from the commercial market, and heat-transfer agents using polychlorinated biphenyls (PCBs), which form dioxins during combustion, are being phased out of production and use.

Who's at Risk

❑ Workers in the chemical industry may have increased likelihood of exposure.

❑ Overt clinical effects from dioxin exposure have been seen primarily after major industrial accidents involving these compounds.

❑ Fetuses and nursing infants may be at increased risk of dioxin exposure if the mothers have been exposed.

Dioxins are no longer manufactured in the United States, except for small amounts used for scientific research. Nevertheless, some workers may encounter dioxins as contaminants in certain industrial processes such as the manufacture of chlorinated herbicides, germicides, and organic solvents. Firefighters and cleanup crews involved with capacitor or transformer fires and hazardous waste accidents may also be exposed to dioxins through dermal absorption or inhalation. Municipal and waste incinerator workers may encounter dioxins in smoke, gases, or fly ash formed during combustion processes. Major industrial accidents have been the source of most overt clinical effects from dioxins.

Because TCDD crosses the placenta and accumulates in breast milk, fetuses and nursing infants of contaminated mothers are potentially at increased risk of exposure. Ingestion of contaminated soil due to pica or normal hand-to-mouth activities may contribute to a child's dioxin body burden. No cases of dioxin toxicity have been reported by either of these routes.

Biologic Fate

❑ Dioxins and furans accumulate in adipose tissue.

❑ In animals, the major routes of absorbed TCDD elimination are through lactation and excretion of urine and bile.

Dioxins enter the body by ingestion, inhalation, and dermal absorption. In humans, the following percentages of total absorption have been reported for various exposure routes: inhalation, 25% to 29%; ingestion of contaminated soil, 20% to 26%; and ingestion of contaminated fish, 50% to 80%. Skin was found to absorb up to 3% of the dioxin in contaminated soil.

The metabolic pathway of TCDD for humans has not been established. TCDD orally administered to animals is metabolized relatively slowly, but once metabolites are formed, they are rapidly excreted in the urine and bile. Metabolism is primarily by hepatic detoxification, with the major metabolites consisting of hydroxylated or methoxylated TCDD derivatives, which are then excreted as glucuronide and sulfate conjugates. Unabsorbed TCDD is excreted through direct elimination in the feces. Because of the lipophilic nature of milk, nursing females decrease their body burden of TCDD through lactation. Dioxins distribute to organs according to lipid content and readily accumulate in body fat. In the general population, the background level of TCDD in adipose tissue may be as high as 20 ppt.

The half-life of TCDD ranges from several hours (on the surface of plants) to 7.1 years (in human serum and adipose tissue). On the soil's surface, where TCDD undergoes photodegradation when exposed to ultraviolet light, the half-life is 1 to 3 years. Beneath the soil's surface, the half-life of TCDD can be over 10 years.

Physiologic Effects

❑ Only two effects of dioxin exposure have been confirmed in humans: chloracne and transient mild hepatotoxicity.

Dioxins are very toxic to some animal species, but the evidence for corresponding toxicity in humans has not been established. No deaths due to systemic dioxin toxicity in humans have been reported. Only two clinical effects have been repeatedly observed in exposed populations: chloracne and transient hepatic effects. Soft-tissue sarcomas, lymphomas, peripheral neuropathy, birth defects, and reproductive effects have been studied but remain unconfirmed. Because human dioxin exposure always involves mixed exposures, the specific effects of dioxin are difficult to ascertain.

In some animals, TCDD is a potent carcinogen and causes reproductive effects and birth defects. TCDD's toxicity also appears in animals as pathologic effects in the liver, peripheral nerves, hematopoietic and reticuloendothelial systems, and skin. Acute toxicity develops after a latent period of 7 to 10 days, after which the animals experience a rapid wasting syndrome not seen in humans.

Clinical Evaluation

Treatment and Management

❑ No antidote for dioxin toxicity is known; symptomatic and supportive care is the only therapy.

Treatment of chronic exposure to dioxin-containing agents is primarily supportive, and depends on the agent involved and the presenting signs and symptoms. It is most important to remove the patient from the source of exposure. Chloracne is often refractory and unresponsive to common acne treatments. Long-term topical treatment with dilute retinoic acid and administration of tetracycline to treat secondary pustular follicles have been used. In severe cases, acne surgery or dermabrasion may be effective.

Standards and Regulations

Before 1965, it was not uncommon for TCDD to be present as a product contaminant in herbicides at concentrations exceeding 30 mg/kg (30ppm). Today, however, the concentration of TCDD as a product contaminant is limited to 0.01 to 0.05 ppm.

Suggested Reading List

Answers to Pretest and Challenge Questions

Pretest is found on page 1. Challenge questions begin on page 4.

(1)

A call to the medical director or the health and safety department of the utility company should provide the answer to the type of herbicide used and its contents. Dioxin-containing herbicides are not likely to have been used in this case since they are no longer being manufactured in the United States.

(2)

The patient could be at increased risk of dioxin exposure because he is living in an area of possible soil contamination. Normal hand-to-mouth activity of children can result in ingestion of contaminated soil. Because of the child's age, it is unlikely that he has pica (the abnormal ingestion of nonfood items, commonly found in children aged 2 to 6 years), which could significantly increase the boy's soil intake. Children consume large quantities of milk, which can be a source of dioxins if it comes from cows grazing on contaminated vegetation. The small amount of dioxin leached from paper milk cartons is negligible.

If the family raises its own foodstuffs and if the previous owner of the farm used contaminated herbicides that still may be present in the soil, the current root crops could contain small amounts of dioxins. (Evidence for translocation of dioxins is sparse and inconclusive.) Even though production of herbicides such as 2,4,5-T were discontinued in the United States in 1976, the half-life of dioxin in soil may be 10 years or more, depending on the type of soil. However, this source is likely to be insignificant in terms of health risk.

(3)

Even if the herbicide did contain dioxins, these compounds photodegrade rapidly, resulting in a half-life on vegetation of several hours and several days in air. The half-life of dioxins in surface soil is 1 to 3 years, while dioxins beneath the soil surface could have a half-life of 10 years or more. However, dermal absorption from TCDD-contaminated soil is less than 5%. If the children do not ingest the soil, the danger is minimal.

(4)

The primary human health effects of dioxin exposure are chloracne, and secondarily, hepatomegaly, elevated liver enzyme levels, and possibly peripheral neuropathy (subclinical changes in nerve conduction velocity).

(5)

Although dioxins are proven carcinogens in some animals, their carcinogenic effect in humans requires further study. Even if the herbicide contained TCDD, the risk of cancer for this patient is likely to be insignificant from a one-time exposure that caused no acute effects.

(6)

Some of the issues you might address in obtaining the medical history are the following: the type and extent of farming carried on by the family; their lifestyle before coming to this farm; dietary habits, including present or past pica in the child.

(7)

During the physical examination, the skin should be carefully examined for evidence of rash, particularly chloracne. Chloracne is a papular, sometimes pustular, lesion located principally on the upper facial areas. The onset of chloracne is not acute, as was the rash described in the case study. In addition, an examination of the abdomen should be conducted, looking for hepatomegaly or hepatic tenderness. A neurologic examination might also be undertaken, with a mental status examination to assess more subtle CNS effects.

(8)

Analytical tests for TCDD (adipose tissue, serum) are very specialized and expensive, and generally are not recommended in clinical practice, especially since interpretation in individual cases is difficult. Dioxins may be associated with hepatotoxicity, and liver function tests would be appropriate if there has been known exposure to dioxin.

(9)

Symptoms associated with acute exposure to dioxin-containing substances include skin and mucous membrane irritation, headache, fatigue, abdominal pain, memory and personality changes, and insomnia. However, such symptoms are nonspecific and may have other etiologies.

(10)

The cause of the child's rash is more likely to be poison ivy, which is common in the wooded areas of the Midwest, an allergy, or exposure to some chemical other than a dioxin. This conclusion is suggested by the acute onset of the rash, its appearance, and its burning nature. Referral to a dermatologist may be warranted if standard measures of treating the rash are not efficacious. The child's symptoms of headache and stomachache may be a result of such factors as stress, food intolerance, or viral infection. If symptoms do not resolve within a day or two, further investigation may be warranted.

Case Study

Disorientation, ataxia, and abdominal symptoms in visitors to a municipal airport

A 67-year-old man is brought to the Emergency Department (ED) of a small community hospital where you are the family physician on call. The patient is experiencing ataxia, dizziness, and vomiting. He is hyperventilating. On physical examination, the patient appears well nourished, agitated, and disoriented. There is no odor of ethanol on his breath. His vital signs include blood pressure, 120/80 mm Hg; temperature, 98.5°F; pulse, 80 beats/minute; and respirations, 40 breaths/minute. Neurologic examination is normal, and there is no nystagmus. Abdominal and cardiorespiratory examinations are also normal.

The patient was brought to the ED by his friend, who relates that the patient said he felt dizzy and began vomiting late last night. This morning he was hyperventilating and continued to vomit. Both men are retired pilots who teach at the ground school at the local airport. Because two other people had collapsed at the airport that morning and were taken by ambulance to another hospital, the friend wonders if the food at the airport cafeteria is responsible. Both he and the patient had hot dogs and coleslaw; yet the friend states that he feels fine.

Although the friend insists that the patient drank only water all day, you order a blood ethanol level, as well as a drug screen, arterial blood gases (ABG), serum electrolytes, BUN, creatinine, and glucose. Blood ethanol and drug screen are negative, and ABG results reveal pH 7.10; Paco₂1 20 mm Hg; and Pao₂ 95 mm Hg. Other test results are sodium, 145 mEq/L; potassium, 3.8 mEq/L; chloride, 105 mEq/L; bicarbonate, 8 mEq/L; BUN, 20 mg/dL; creatinine, 1.0 mg/dL; and glucose, 80 mg/dL. The calculated anion gap is 32 (normal 12 to 16).

Less than 30 minutes later, a 4-year-old boy is brought to the ED. On examination, you find a sleepy but arousable child. There is no evidence of trauma or focal neurologic signs. Abdominal and cardiorespiratory examinations are normal. Vital signs include rectal temperature, 97.8°F; respirations, 12 breaths/minute; pulse, 78 beats/minute; BP, 94/76 mm Hg. The parents tell you that they were attending a local fliers' club luncheon at the airport. When they found the child staggering and incoherent, they rushed him to the ED; the child vomited in the car. You order the same laboratory tests for the child that you ordered for the 67-year-old patient. From the results of the child's tests, you note that the child is hypoglycemic and slightly acidotic. You calculate an anion gap of 13.

You contact the local health department and are told that they are investigating the earlier incidents at the airport. They suspect that the airport's water supply is contaminated, but they have not identified the contaminant.

(a) What would you include in each patient's problem list? What is the differential diagnosis for an anion gap metabolic acidosis?

_________________________________________________________________

_________________________________________________________________

_________________________________________________________________

(b) What additional tests, if any, will you order for these patients?

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(c) How will you initially treat these patients?

_________________________________________________________________

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Answers to the Pretest questions are on page 21.

Glycol Properties

Ethylene glycol and propylene glycol are manufactured chemicals that have similar physical properties and uses. Their chemical structures differ by only one methyl group (ethylene glycol, HOCH₂CH₂OH; propylene glycol, CH₃CH[OH]CH₂OH). Both chemicals are clear, colorless, odorless, sweet-tasting, highly viscous liquids. They have low vapor pressures at room temperature, indicating low potential for inhalation exposure.

Despite similarities in physical properties and chemical structure, ethylene glycol and propylene glycol have vastly different toxicities. Ethylene glycol is acutely toxic to humans, whereas propylene glycol is a safe additive for foods and medications. Propylene glycol causes poisoning only rarely and under unusual circumstances. These glycols should not be confused with glycol ethers (e.g., ethylene glycol monomethyl ether, also known as methyl cellosolve, and ethylene glycol monoethyl ether), which are suspected reproductive and developmental toxicants. A discussion of ethylene glycol follows; discussion of propylene glycol begins on page 18.

Ethylene Glycol Exposure Pathways

❑ Antifreeze, which can contain up to 95% ethylene glycol, is the most common source of ethylene glycol overexposure.

Ethylene glycol is used in many industries because it has the ability to absorb water and to prevent overheating or freezing. It is used extensively in automotive fluids such as antifreeze, coolants, and hydraulic fluids. Antifreeze, which typically consists of 95% ethylene glycol, accounts for about 65% of the ethylene glycol produced. Ethylene glycol is also used in cosmetics, fat extractants, and as a chemical intermediate. As a solvent, it is found in inks, stains, pesticides, fire extinguishers, foams, polishes, and adhesives. Its heat-regulation properties are employed in air conditioning units and solar energy systems.

Synonyms for ethylene glycol include ethylene alcohol, glycol alcohol, glycol, 1,2-dihydroxyethane, and 1,2-ethanediol. Commercial products containing high concentrations of ethylene glycol include Dowtherm SR1^*, Lutrol-9, Norkool, Tescol, and UCAR-17.

Waste streams produced when ethylene glycol is manufactured or used account for the most significant releases of this compound into the environment. In military and commercial aviation, large amounts of ethylene glycol are used for deicing. It is sprayed as an aerosol or mist onto airplane wings to prevent ice buildup. Used in this manner, ethylene glycol can contaminate groundwater near airports through runoff and may expose workers to air levels ranging from <0.05 milligrams per cubic meter (mg/m³) to 10.4 mg/m³ (i.e., <0.02 parts per million [ppm] to 4.2 ppm). The Occupational Safety and Health Administration (OSHA) ceiling limit (15-minute sample) for ethylene glycol is 125 mg/m³ or 50 ppm. Ethylene glycol is also used in coolant loops in spacecraft and in aviator protective clothing; both applications present potential for exposure if leaks occur.

❑ Because of its low vapor pressure and poor skin absorption, ethylene glycol poisonings normally occur by ingestion.

❑ Ethylene glycol rapidly degrades in the environment.

Ethylene glycol does not persist in ambient air in large amounts because breakdown is rapid (half-life in air is 24 to 50 hours). Its low vapor pressure precludes substantial inhalation exposure at ambient temperatures, and its poor skin absorption prevents significant absorption after dermal contact. Ethylene glycol is miscible with water and adheres to soil (half-life in water and soil is several days). Because it is not fat-soluble, bioconcentration and bioaccumulation are insignificant.

Who's at Risk

❑ Workers in industries producing or using products that contain ethylene glycol are at greatest risk of exposure.

Workers in industries that manufacture or use products containing ethylene glycol, particularly operations involving automobile maintenance and aircraft deicing, are at greatest risk of exposure. Although dermal contact is the main route of occupational exposure, vapors or mists can be inhaled when the chemical is heated, agitated, or sprayed.

❑ The general population has risk of exposure to ethylene glycol primarily through contact with automobile antifreezes and coolants.

There have been no reports of adverse health effects from chronic environmental exposures to ethylene glycol, and few data exist to evaluate such effects from these exposure scenarios. In the general population, ethylene glycol exposure occurs most commonly through accidental or intentional ingestion of antifreeze. During 1990, 3,242 cases of ethylene glycol exposure were reported to the 72 poison centers participating in the National Data Collection System of the American Association of Poison Control Centers. Of these, 1,451 patients (45%) were examined in health care facilities, 1,147 (35%) became symptomatic, 62 (2%) developed major symptoms, and 5 (0.2%) died. The remainder (577[17.8%]) suffered no ill effects. The general population can also be exposed to ethylene glycol by dermal contact while handling automotive antifreezes, coolants, and brake fluids; however, such exposure is not likely to cause adverse health effects under normal conditions.

Biologic Fate

❑ Absorption of ethylene glycol by the gastrointestinal tract is rapid; dermal absorption is slow. Inhalation is not an important route of exposure under normal conditions of use.

Ethylene glycol is rapidly absorbed by the gastrointestinal tract, less rapidly by the lungs, and slowly through the skin. Because of ethylene glycol's low vapor pressure, inhalation is generally not associated with toxicity, although neurologic symptoms including nystagmus and syncope were reported in factory workers chronically exposed to vapor from heated ethylene glycol.

Because it is highly water-soluble, ethylene glycol is evenly distributed throughout the body. It reaches peak tissue levels 1 to 4 hours after ingestion. Approximately 24 hours later, no unchanged ethylene glycol is detected in urine or tissues, indicating rapid biotransformation. The normal serum half-life of ethylene glycol is approximately 2.5 hours.

❑ Ethylene glycol is metabolized in the liver to a variety of more toxic compounds.

Although ethylene glycol itself has relatively low toxicity, it is metabolized in the liver to a variety of toxic compounds (Figure 1), some of which have elimination half-lives of up to 12 hours. The rate-limiting step in this metabolic process is the conversion of ethylene glycol to glycoaldehyde. Generally, only a small fraction of ethylene glycol (less than 20% in low-dose ingestions) is excreted unchanged in the urine. However, coadministration of ethanol, which inhibits ethylene glycol metabolism by preferentially reacting with alcohol dehydrogenase, can extend the serum half-life of ethylene glycol to 17 hours and increase the percentage of ethylene glycol that is ultimately excreted unchanged. This mechanism is the basis for the antidotal use of ethanol in ethylene glycol-poisoned patients.

Figure 1.

Metabolism of ethylene glycol

❑ Only a small fraction of absorbed ethylene glycol is normally excreted unchanged in the urine.

Persons who have impaired liver or kidney function, and children, who have immature hepatic detoxification systems, may be at greater risk of ethylene glycol's initial central nervous system (CNS) effects. However, the clinical courses of illness in such patients may be less severe because of decreased abilities to form toxic metabolites.

Adapted from Hall AH. Ethylene glycol and methanol: poisons with toxic metabolic activation. Emergency Medicine Reports 1992;13(4):29–38. Used with permission of the publisher.

Physiologic Effects

Neurobehavioral Effects

❑ Unmetabolized ethylene glycol contributes to CNS depression.

The aldehyde metabolites of ethylene glycol are the cause of many of ethylene glycol's delayed toxic effects. These metabolites inhibit oxidative phosphorylation; cellular respiration; and glucose, protein, and serotonin metabolism. In addition, accumulation of glycolic acid, glyoxylic acid, and, to a lesser extent, oxalic acid, results in metabolic acidosis. (Lactic acid formed during the metabolism of ethylene glycol to oxalic acid also contributes to the metabolic acidosis in patients poisoned by this glycol.)

❑ Delayed clinical toxicity results from the conversion of ethylene glycol to more toxic metabolites.

Ethylene glycol poisoning typically has three phases (Table 1). Phase 1, which begins 30 minutes to 12 hours after ingestion, includes signs of inebriation and CNS depression from unmetabolized ethylene glycol and from aldehyde metabolites that peak 6 to 12 hours after ingestion. In some cases, cerebral edema develops. Signs of metabolic acidosis may become apparent late in Phase 1.

Table 1.

Clinical course in acute ethylene glycol intoxication.

Phase 2, the cardiopulmonary toxicity phase, begins 12 to 24 hours after ingestion. Deposition of calcium oxalate crystals can cause tissue injury in various sites including the meninges of the brain, vascular tree, myocardium, and lung parenchyma. Hypocalcemia may occur secondary to the precipitation of calcium by the oxalate metabolite.

Phase 3, which begins 24 to 72 hours after ingestion, can be manifested by a profound metabolic acidosis. Deposition of calcium oxalate crystals in the kidneys can lead to acute renal failure (irreversible in some cases) and hyperkalemia.

The minimum lethal ingested dose of antifreeze (95% ethylene glycol) for adults is approximately 1.4 mL/kg body weight or about 100 mL of antifreeze for a 70-kg person, although persons who attempted suicide by ingesting 1 to 2 liters of the 95% solution and were treated within 1 hour have survived.

Clinical Evaluation

History and Physical Examination

❑ A detailed history is important in diagnosing ethylene glycol poisoning.

Ethylene glycol ingestion is a medical emergency requiring prompt recognition and aggressive treatment for a good outcome. The clinical picture in ethylene glycol poisoning varies based upon the amount ingested, the time elapsed since ingestion, and the concurrent ingestion of large amounts of ethanol. Making a correct decision regarding treatment requires a reliable history of the time, route, and magnitude of exposure. However, a detailed history can be difficult to obtain because patients often have an altered mental state. If ethylene glycol poisoning is strongly suspected, supportive and specific treatment should be instituted pending confirmatory laboratory results.

❑ Prompt recognition and early therapeutic intervention are essential to preventing latent effects and potential sequelae of ethylene glycol poisoning.

Although there is concern about environmental exposures to ethylene glycol, nearly all cases of ethylene glycol poisoning are due to ingestions. A history of alcohol abuse may suggest ingestion of ethylene glycol as an ethanol substitute. A meticulous search in the home for ethylene glycol-containing compounds should be made in all suspected poisonings. If a product label does not list the chemical ingredients, the regional poison control center may be able to assist. Inquiring about similar symptoms in family members, friends, and coworkers may be helpful in identifying a common source of exposure.

The patient's vital signs should be monitored. Although not specific for ethylene glycol intoxication, hypertension, tachycardia, and low-grade fever have been associated with moderate or severe poisoning. A complete neurologic examination should be performed with special attention directed to gait and balance.

Numerous exogenous toxic substances are associated with an elevated anion gap (Table 2). Only four conditions will cause metabolic acidosis and elevate both the anion and osmolal gaps— methanol poisoning, ethylene glycol poisoning, alcoholic ketoacidosis, and diabetic coma. However, when large quantities of ethanol are ingested concomitantly with ethylene glycol, enzymatic conversion to toxic metabolites that produce metabolic acidosis will be inhibited. Inhibiting metabolism also increases the amount of unchanged ethylene glycol circulating in the body. Hence, a patient who has concomitantly ingested ethanol could have an elevated osmolal gap without an elevated anion gap early in the clinical course. The presence of metabolic acidosis and either an anion or osmolal gap should alert the clinician to the possibility of ethylene glycol poisoning.

Table 2.

Common toxic agents associated with an elevated anion gap.

Laboratory Tests

❑ An elevated anion-gap metabolic acidosis and an elevated osmolal gap combined with urinary crystals suggest ethylene glycol poisoning.

❑ Measurement of serum ethylene glycol levels can confirm poisoning.

The abnormal laboratory findings in ethylene glycol poisoning include an elevated anion-gap metabolic acidosis, an increased osmolal gap, elevated serum ethylene glycol level, calcium oxalate or hippurate crystalluria, and sometimes, hypocalcemia. Arterial blood gases, blood glucose, serum electrolytes, and blood ethanol should be measured in all patients with histories of ethylene glycol ingestion or in whom poisoning is suspected. Results of these laboratory tests will confirm the presence and degree of metabolic acidosis and allow calculation of the anion and osmolal gaps (Table 3). A blood ethanol level will establish whether initial CNS symptoms are due to ethanol. The presence of ethanol will also have a substantial impact on metabolism and therapy.

Table 3.

Formulas for calculating anion and osmolal gaps.

The presence of calcium oxalate or hippurate crystals in the urine, together with an elevated anion gap or osmolal gap, strongly suggests ethylene glycol poisoning. Urinary crystals result from the precipitation of calcium by the oxalic acid metabolite of ethylene glycol or from the reaction of the glycine metabolite with benzoic acid, which forms hippuric acid. The crystals can take many forms including dumbbells, envelopes, or most commonly, needles. Absence of urinary crystals, however, does not rule out poisoning. Because some antifreeze products contain fluorescein, the urine may fluoresce under a Wood's lamp.

An elevated serum level of ethylene glycol confirms ethylene glycol poisoning; significant toxicity is associated with levels greater than 50 mg/dL. Communication with the laboratory is critical in poisoning cases because 2,3-butanediol often found in the plasma of alcoholics can be mistakenly identified as ethylene glycol when the analysis is performed by gas chromatography. Furthermore, propylene glycol may interfere with some assays for ethylene glycol.

(5) What additional laboratory tests will you order for the man and child described in the case study on page 1?

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_________________________________________________________________

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Treatment and Management

❑ Correction of metabolic acidosis is an important part of treatment in ethylene glycol poisoning.

Treatment should not be delayed pending results of ethylene glycol serum levels if the clinical picture is severe or if the history suggests such poisoning. Treatment advice can be obtained from a regional poison control center or medical toxicologist

Initial management of suspected poisoning includes basic life support with intubation and mechanical ventilation if required. When the ingestion is recent, measures to prevent ethylene glycol absorption should be taken if the patient's level of consciousness permits. Induced emesis or gastric lavage may be useful if ingestion occurred within 1 to 2 hours. Activated charcoal is not likely to be effective because it does not adsorb ethylene glycol well.

❑ Specific treatments for ethylene glycol poisoning are ethanol therapy and hemodialysis.

Specific treatment for ethylene glycol poisoning consists of sodium bicarbonate to correct the metabolic acidosis, ethanol to competitively inhibit conversion of ethylene glycol to its more toxic metabolites, and hemodialysis to remove ethylene glycol and glycolic acid. Although this treatment regimen is effective in most cases, renal failure and death can occur if treatment is delayed.

Ethanol is used to saturate the alcohol dehydrogenase enzyme so that ethylene glycol is maintained in an unmetabolized form and excreted unchanged in the urine. Ethanol therapy should be considered when ethylene glycol levels are greater than 20 mg/dL or when ethylene glycol poisoning is strongly suspected. Patients who have a history of concurrent ethanol ingestion, or who are undergoing hemodialysis, require dosage modification (Table 4). Ethanol can cause hypoglycemia, particularly in children; therefore, blood glucose should be monitored closely. The hypoglycemia that develops in adults is often overlooked because the impairment of mental status is attributed to the ethanol.

Table 4.

Intravenous administration of ethanol in ethylene glycol and methanol poisoning.

The loading dose and the maintenance dose should be infused over the first hour of therapy. Decrease to only the maintenance dose in the second hour. If the drinking habits of a patient cannot be determined from the history, assume the patient is in the category of “social drinker,” then adjust the dose to achieve a blood ethanol level that remains between 100 and 150 mg/dL.

To prepare 1 liter of 10% ethanol in 5% dextrose in distilled water (D₅W) for intravenous infusion, perform either of the following steps:

1.

Remove 100 mL of fluid from 1 liter of D₅W; replace with 100 mL of absolute ethanol, or

2.

Remove 50 mL of fluid from 1 liter of commercially available 5% ethanol in D₅W solution; replace with 50 mL of absolute ethanol.

Blood ethanol and serum glucose levels should be monitored at the end of the loading dose and hourly until the maintenance dose is adjusted. Both should then be monitored two to three times daily, but more frequently during dialysis.

Hemodialysis should be considered if serum ethylene glycol levels exceed 50 mg/dL, if severe acid/base or fluid/electrolyte disturbances persist despite decontamination and ethanol therapy, or if renal failure develops. Hemodialysis should be continued until acidosis is controlled and the serum ethylene glycol level is in the 10 to 15 mg/dL range. Ethanol therapy can be discontinued when the serum ethylene glycol level is below this range.

Thiamine and pyridoxine, two water-soluble B complex vitamins that act as metabolic cofactors, are commonly administered to patients who have ethylene glycol toxicity. Pyridoxine is administered intravenously (100 mg or 1 mg/kg daily until intoxication is resolved). If the vitamins are administered before dialysis, the dose should be repeated after dialysis because they are highly water-soluble and are likely to be removed by the procedure. Thiamine is administered intravenously (100 mg or 1 mg/kg daily) until intoxication is resolved. These cofactors help convert ethylene glycol to less toxic metabolites and may decrease the formation of oxalate.

4-Methylpyrazole is a specific inhibitor of the alcohol dehydrogenase enzyme. It has low toxicity and may replace ethanol in the treatment of ethylene glycol poisoning. At present, 4-methylpyrazole is undergoing clinical trials and is available in the United States only for investigational use.

Standards and Regulations

Propylene Glycol Exposure Pathways

❑ Propylene glycol is used in various foods, cosmetics, and pharmaceutical products.

FDA classifies propylene glycol as a Generally Recognized as Safe (GRAS) additive. Propylene glycol acts as an emulsifying agent, humectant, surfactant, and solvent in certain medicines, cosmetics, and food products. Concentrations in foods range from <0.001% in eggs and soups to about 15% in some seasonings and flavorings. The largest amounts of propylene glycol are used in the textile industry, where it is an intermediate in polyester fiber production. Synonyms for propylene glycol include 1,2-propanediol, 1,2-dihydroxypropane, methyl glycol, and trimethyl glycol.

The military uses aerosolized propylene glycol as a smoke screen on the battlefield to conceal the movement of troops. Because it can provide dense smoke without flames, it is also a smoke simulator in various types of fire-training materials. Propylene glycol is sometimes used as a deicing agent; however, ethylene glycol is used more often because it costs less. Propylene glycol is an FDA-approved additive for military dietary rations.

In the general population, propylene glycol exposure occurs primarily through ingestion of food and medications and through dermal contact with cosmetics or topical medications. No adverse health effects are likely to occur from normal use of these products.

Who's at Risk

❑ Propylene glycol toxicity is not expected in normal environmental or occupational exposures.

Propylene glycol toxicity has been reported only rarely and in unusual circumstances involving medical applications such as intravenous injection or prolonged dermal contact during treatment of burns. (See Physiologic Effects, page 19.)

Biologic Fate

❑ Propylene glycol is metabolized to compounds that are normal constituents of the citric acid cycle.

Absorption of propylene glycol from the gastrointestinal tract is rapid, with maximal plasma concentrations in humans occurring within 1 hour after ingestion. Propylene glycol is metabolized in the liver by alcohol dehydrogenase to lactic acid, then to pyruvic acid. Both of these metabolites are normal constituents of the citric acid cycle and are further metabolized to carbon dioxide and water. About 45% of an absorbed propylene glycol dose is excreted by the kidneys unchanged or as the glucuronide conjugate. The elimination half-life of propylene glycol is about 4 hours.

Physiologic Effects

❑ Large doses and unusual circumstances are necessary for the development of propylene glycol toxicity.

CNS depression is the primary manifestation of acute propylene glycol poisoning. Metabolic conversion of propylene glycol to lactic and pyruvic acids can contribute to metabolic acidosis with an abnormal anion gap. Unchanged propylene glycol circulating in the body causes hyperosmolality.

❑ Propylene glycol poisoning is marked initially by CNS depression and an elevated osmolal gap, and later by an increased anion gap.

Although propylene glycol is nontoxic under normal conditions, it can cause poisoning in rare and unusual circumstances. In one case, an 8-month-old infant with large surface area second- and third-degree burns was treated for many days with topical silver sulfadiazine containing a large amount of propylene glycol. The infant developed acute metabolic acidosis and cardiorespiratory arrest. The dose of propylene glycol was 9,000 mg/kg/day. Serum propylene glycol levels were highest on day 14 (1,059 mg/dL) when the osmolal gap was 75 mOsm/L (normal: <10 mOsm/L).

❑ Unlike ethylene glycol, propylene glycol does not produce nephrotoxicity in humans.

Propylene glycol is a common diluent for injectable medications and constitutes 40% of the intravenous form of phenytoin. This high concentration is necessary to maintain a stable preparation and to prevent precipitation of phenytoin crystals. In some patients given intravenous phenytoin, propylene glycol was reported to cause hypotension, cardiac conduction disturbances, and cardiac dysrhythmias; fatal cardiac and respiratory arrests have been reported.

Propylene glycol has not been associated with nephrotoxicity in humans. Unlike ethylene glycol, propylene glycol is not metabolized to oxalic acid with subsequent deposition of calcium oxalate in the kidneys.

Clinical Evaluation, Treatment, and Management

❑ Treatment for propylene glycol poisoning is supportive and involves hemodialysis and correction of metabolic acidosis using sodium bicarbonate therapy.

Although the toxicity of propylene glycol is low, if large amounts are absorbed, an elevated osmolal gap may result. Because propylene glycol is metabolized to lactic acid, ingestion of massive doses of propylene glycol can cause severe metabolic acidosis. Coma, seizures, and hypoglycemia rarely develop in patients with propylene glycol intoxication. Cardiac monitoring is needed if other symptoms are present.

Metabolic acidosis caused by ingestion of large amounts of propylene glycol can be corrected with sodium bicarbonate therapy. Hemodialysis is effective in correcting hyperosmolality by removing propylene glycol from the blood. Ethanol therapy, as described for ethylene glycol-poisoned patients, is unnecessary for patients with propylene glycol poisoning.

Standards and Regulations

There are no workplace or environmental standards for propylene glycol. FDA considers an average daily dietary intake of 23 mg/kg of body weight to be safe for persons 2 to 65 years of age.

Suggested Reading List

Sources of Information

More information on the adverse effects of ethylene glycol and propylene glycol and treating cases of exposure to these glycols can be obtained from ATSDR, your state and local health departments, and university medical centers. Case Studies in Environmental Medicine: Ethylene/Propylene Glycol Toxicity is one of a series. To obtain other publications in this series, please use the order form on the inside back cover. For clinical inquiries, contact ATSDR, Division of Health Education, Office of the Director, at (404) 639–6204.

Answers to Pretest and Challenge Questions

Pretest questions are on page 1. Challenge questions begin on page 3.

Case 1

This patient was a 41-year-old nursing sister who began working with formalin in a renal dialysis unit in 1969. She developed a persistent dry cough and episodic attacks of wheezing within a few months which were not improved when she stopped smoking. On two occasions wheezing began four to five hours after exposure for five to 20 minutes to spilled undiluted formalin B.P.C. (34–38% solution of formaldehyde in water w/w). There were no other obvious provoking factors. In 1973 her wheezing, accompanied by increasing breathlessness and rhinitis, became persistent and her cough became productive. Treatment with antibiotics and bronchodilators brought little relief and in June 1973 she was obliged to take sick leave, during which she slowly recovered. A chest x-ray film showed inflammatory changes in the apical segment of the right lower lobe. The haemoglobin was 13·4 g/dl and the W.B.C. was 13·1×10⁹/1 (13 100/mm³), of which 2·1×10⁹/1 (2100/mm³) were eosinophils. Routine skin prick tests with 12 common allergens proved negative.

Inhalation provocation tests were begun one month later, when she was receiving no medication. She simulated occupational exposure by “painting” formalin on identical cardboard pieces on different mornings within a confined space. A nose clip prevented her recognizing 25% but not 100% formalin. Ventilatory function was monitored by measurement of forced expiratory volume in one second (FEV₁) using a dry spirometer (Vitalograph) or peak expiratory flow (PEF) using a Wright's meter. The results, expressed as % change, are shown in fig. 1. The late asthmatic reaction seen in test 1 persisted for some days and like that of test 3 showed little objective response to inhaled salbutamol. It was inhibited by prior inhalation of betamethasone 17-valerate 200 µg (test 4). There was no febrile response or significant change in W.B.C. or eosinophil count after any of these tests.

FIG. 1

Case 1. Results of inhalation provocation tests. Values in parentheses are readings obtained immediately before each exposure.

After these studies extractor fans were fitted to the dialysis unit, and undiluted formalin was handled more carefully. The nurse avoided unnecessary exposure and, in particular, no longer cleared up spilled undiluted formalin herself. With these measures her symptoms were completely relieved and she needed no medication.

Case 2

A 59-year-old pathologist had suffered mild asthma as a child and hay fever from the age of 19. Airways obstruction had recurred in 1970 and been slowly progressive ever since. He smoked a pipe and had worked with formalin continually for 17 years. He thought that prolonged exposures worsened his symptoms during the evening after. Routine investigations showed an eosinophilia of 1·19×10⁹/1 (1188/mm³), and a skin-prick test produced a positive reaction to grass pollen. There was no other abnormality.

Inhalation provocation tests were conducted as in case 1. Increasing exposures to formalin produced no febrile or haematological response and no significant change in the pattern of ventilatory function from that shown on a control day (fig. 2). The exposure of test 4 was thought to have exceeded the daily maximum encountered naturally in the course of his work. He may consequently be regarded as a control to case 1.

FIG. 2

Case 2. Results of inhalation provocation tests. Values in parentheses are readings obtained immediately before each exposure.

Comment

The value of inhalation provocation tests as an adjunct to a carefully taken occupational history in the investigation of airways obstruction is well illustrated by these two cases. The suspected aetiological role of formalin was confirmed in one patient but excluded in the other. As a result measures of environmental control were introduced where appropriate, with good effect.

The responses observed in case 1 seemed to be specific asthmatic reactions to formalin fumes. They began between two and four hours after exposure was begun. The greater the exposure the longer the reaction persisted, though the maximum percentage fall in ventilatory function was similar, provided exposure was sufficiently prolonged to provoke a positive response. Similar late asthmatic reactions have been described after the inhalation of fumes of other chemicals, including tolylene di-isocyanate (Pepys et al., 1972) and aminoethyl ethanolamine (Sterling, 1967; Pepys and Pickering, 1972). Such reactions may be inhibited by the prior inhalation of corticosteroid aerosols (Pepys et al., 1974), and this was confirmed in our patient though subsequent treatment did not in the event prove

We thank the medical illustration department, Radcliffe Infirmary, for the illustrations.

References

• Kotin, P., and Falk, H.L. (1964). Annual Review of Medicine , 15, 233. [PubMed: 14133847]
• Pepys, J., et al. (1972). Clinical Allergy , 2 , 225 . [PubMed: 4643785]
• Pepys, J., and Pickering, C.A.C. (1972). Clinical Allergy , 2, 197. [PubMed: 4632184]
• Pepys, J., et al. (1974). Clinical Allergy , 4, 13. [PubMed: 4363220]
• Popa, V., et al. (1969). Diseases of the Chest , 56, 395. [PubMed: 5347248]
• Sterling, G.M. (1967). Thorax , 22 , 533. [PMC free article: PMC471707] [PubMed: 6076508]
• Vaughan, W.T. (1939). The Practice of Allergy , p. 677. St. Louis, Mosby.

Case Study

A 29-year-old auto mechanic with headaches, irritability, and forgetfulness

A 29-year-old man is brought to your office by his wife. He is reluctant to provide a history but does admit that he has been having frequent headaches for the past month. His wife indicates that at times he is somewhat confused and forgetful. She feels these symptoms have developed since they moved to their new home 6 months ago. She tells you that she has also been irritable and that several of their neighbors have been complaining of a variety of nonspecific symptoms, including headaches and forgetfulness. The wife also says that a nearby gas station was recently fined for having a leaking underground storage tank, and she feels that her family and her neighbors are being poisoned by contaminated drinking water.

The patient's medical history is unremarkable. After completing high school, he entered the Air Force, where he was trained as a mechanic. When he left military service, he and his family moved back to this rural community to be close to his wife's family. He has taken a job at the hardware store as a temporary position and plans to open an automotive repair shop within the next year. He has had an interest in old automobiles since high school. His new position at the hardware store has allowed him to spend an increasing amount of time working on old cars in his garage in back of the house.

The patient's physical examination is unremarkable except for mild dermatitis on the hands, which he attributes to grease and the dirty auto parts he handles. Results of laboratory screening tests, including CBC and liver function tests, are within normal limits.

(a) What further questions would you ask regarding the wife's and neighbors' symptoms?

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(b) What further questions would you ask regarding the patient's work at the hardware store and his automobile-related hobby?

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(c) What additional data would be informative regarding the leaking storage tank mentioned by the patient's wife?

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Answers to the Pretest questions are on page 19.

Exposure Pathways

❑ The principal exposure to gasoline for the general population is through vapor inhalation during automobile refueling.

Gasoline is a refined petroleum product that is used as a motor fuel. It is highly flammable and potentially explosive. It contains more than 250 hydrocarbons and small quantities of additives and blending agents. The composition of gasoline varies depending on geographic region, season, performance requirements, and blending stocks. The typical hydrocarbon content of liquid gasoline (% volume) is as follows: approximately 60% to 70% alkanes (straight chain, branched chain, and cyclic), 5% to 10% alkenes (straight chain and branched chain), and 25% to 30% aromatics (Figure 1).

Figure 1.

Chemical structures for typical members of the three major classes of hydrocarbons in gasoline.

Benzene, a known hematotoxic agent, is present at an average concentration of approximately 1% in U.S. gasoline but can be as high as 5% concentration in European formulations. In addition to hydrocarbons, gasoline contains additives to improve its performance as a motor fuel and to enhance its stability. These additives include antioxidants, metal deactivators, antirust agents, anti-icing agents, detergents, dyes, and antiknock agents (which prevent detonation during combustion in internal-combustion engines and ensure smooth, even burning within the combustion cylinder).

❑ Gasoline misuse or abuse is a serious exposure concern.

Gasoline that contains more than 0.05 grams of lead per gram of gasoline is considered leaded gasoline. Organic lead is added to enhance a fuel's octane rating. (The octane rating compares the antiknock properties of a liquid motor fuel to an industry standard; the higher the rating, the more likely the fuel will burn evenly in the combustion chamber.) In 1989, only 10% of the gasoline purchased in the United States was leaded gasoline. Due to the mandated phaseout of leaded gasoline in the United States, this percentage is rapidly decreasing. By 1997, the use of leaded gasoline in this country will have virtually ceased. However, organic lead compounds are still added to gasoline in other parts of the world. The presence of organic lead compounds in gasoline requires the addition of lead-scavenging agents such as ethylene dibromide (EDB). The replacements for organic lead antiknock agents include ethanol, methanol, methyl tertiary butyl ether (MTBE), and tertiary butyl ether (TBE), which are typically added in concentrations of 5% to 15%.

The composition of gasoline vapor differs considerably from the composition of liquid gasoline. In general, vapor pressures of the individual ingredients of liquid gasoline determine the composition of the gasoline vapor. Analysis of the major components in the liquid and vapor phases of a typical blend of the gasoline shows that while the liquid contains about 60% total alkanes, the vapor consists of nearly 90% alkanes (mainly the lighter C₄-C₅ components). Aromatic compounds represent 30% of the liquid phase, compared with only about 2% of the vapor phase. Benzene that is 2.1 % of the liquid phase constitutes about 0.9% of the vapor phase. n-Hexane, a neurotoxic agent, is about 2.7% of the liquid phase and 0.9% of the vapor phase. Gasoline additives can also be present in the vapor phase but usually in small amounts.

Who's at Risk

❑ Workers in bulk terminals and on marine tankers, tank-truck drivers, auto mechanics, and service-station attendants have the greatest occupational risk of gasoline exposure.

The gasoline manufacturing and distribution system involves production of gasoline at oil refineries; transportation via truck, rail, barge, or pipeline to bulk terminals; and further movement from bulk terminals to retail gasoline stations. Refinery workers, persons associated with transportation, gasoline service-station attendants, and workers involved in removal and maintenance of underground storage tanks are at greatest risk of exposure to gasoline. Persons living near gasoline production and distribution systems also have potential exposure. Health risk among consumers and the general public from gasoline-vapor exposure during refueling at self-service gasoline stations is probably negligible.

Persons who misuse gasoline to clean garage floors or use gasoline-soaked rags to clean hands or machinery parts risk toxicity from both inhalation and dermal absorption. Persons who unintentionally ingest gasoline while siphoning and those who intentionally inhale gasoline vapors to obtain euphoric effects risk serious health consequences. The highly flammable and explosive nature of gasoline increases its risk, especially during misuse. Although it is illegal to smoke near a gasoline source, many persons do so, placing themselves and others in great danger. Using gasoline to ignite fires or to increase their rate of burning is also hazardous.

❑ Persons who misuse gasoline as a recreational drug are at substantial risk for adverse effects.

Persons who ingest gasoline-contaminated groundwater are at risk of exposure, but the health risks of chronic ingestion of gasoline are unknown. Although numerous cases of leaking underground storage tanks have been documented, contaminated water supplies have rarely contained the individual components of gasoline at concentrations that exceed the EPA maximum contaminant levels.

Persons susceptible to gasoline toxicity include the very young, the very old, pregnant women, and persons suffering from malnutrition.

Biologic Fate

❑ The most common routes of gasoline exposure are inhalation and dermal absorption.

The data on the toxicokinetics of gasoline mixtures in humans or animals are sparse. Studies on several of the hydrocarbon components of gasoline are readily available (see Case Studies in Environmental Medicine: Benzene Toxicity and Case Studies in Environmental Medicine: Toluene Toxicity ) and on some additives (see Case Studies in Environmental Medicine: Methanol Toxicity and Case Studies in Environmental Medicine: Lead Toxicity ). However, the interaction of the components in a gasoline mixture may influence the absorption, distribution, metabolism, and elimination patterns of the individual components.

Physiologic Effects

The major target organ of gasoline exposure is the central nervous system (CNS). Inhalation is the most common route of exposure. Ingestion can result in severe toxicity; single oral doses of approximately 10 milliliters per kilogram (mL/kg) body weight (or about 700 mL for an adult) may be fatal. Much smaller amounts, if aspirated into the lungs, may lead to lipoid pneumonitis.

Contact with liquid gasoline can cause an acute burning sensation in the skin, eyes, and mucous membranes. Prolonged contact with liquid gasoline can defat the skin and cause irritation and dermatitis. Absorption of gasoline probably increases if the skin is broken. Systemic gasoline poisoning due solely to skin exposure has not been documented conclusively.

Clinical Evaluation

Treatment and Management

Standards and Regulations

Workplace

Air

❑ The current OSHA workplace standard is 300 ppm (8-hr TWA).

The Occupational Safety and Health Administration (OSHA) mandates permissible limits for occupational exposures. The permissible exposure limit (PEL) for gasoline is 300 ppm as an 8-hour time-weighted average (TWA) and 500 ppm as a short-term exposure limit (STEL). (See Table 1.)

Table 1.

Standards and regulations for gasoline.

Suggested Reading List