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3 Methylene Chloride Toxicity

Environmental ALERT…

The effects of acute exposure to methylene chloride (dichloromethane) are due to its CNS depressant properties, which have resulted in fatalities.

Metabolic conversion of methylene chloride to carbon monoxide may place persons with pre-existing coronary artery disease at increased risk.

EPA considers methylene chloride to be a probable human carcinogen.

This monograph is one in a series of self-instructional publications designed to increase the primary care provider’s knowledge of hazardous substances in the environment and to aid in the evaluation of potentially exposed patients. The Agency for Toxic Substances and Disease Control (ATSDR) and the Centers for Disease Control (CDC) designate this continuing medical education activity for 1 credit hour in Category 1 of the Physician’s Recognition Award of the American Medical Association and 0.1 continuing education units for other health professionals. See pages 19 to 21 for further information.

Guest Contributors:

Jon Rosenberg, MD, MPH; Gloria Hathaway, PhD

Guest Editor:

Laura Welch, MD

Peer Reviewers:

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

Bernard Goldstein, MD; Alan Hall, MD;

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

Linda Rosenstock, MD, MPH; Robert Wheater, MS; Brian Wummer, MD

U.S. DEPARTMENT OF HEALTH & HUMAN SERVICES

Public Health Service

Agency for Toxic Substances and Disease Registry



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Environmental Medicine: Integrating a Missing Element into Medical Education 3 Methylene Chloride Toxicity Environmental ALERT… The effects of acute exposure to methylene chloride (dichloromethane) are due to its CNS depressant properties, which have resulted in fatalities. Metabolic conversion of methylene chloride to carbon monoxide may place persons with pre-existing coronary artery disease at increased risk. EPA considers methylene chloride to be a probable human carcinogen. This monograph is one in a series of self-instructional publications designed to increase the primary care provider’s knowledge of hazardous substances in the environment and to aid in the evaluation of potentially exposed patients. The Agency for Toxic Substances and Disease Control (ATSDR) and the Centers for Disease Control (CDC) designate this continuing medical education activity for 1 credit hour in Category 1 of the Physician’s Recognition Award of the American Medical Association and 0.1 continuing education units for other health professionals. See pages 19 to 21 for further information. Guest Contributors: Jon Rosenberg, MD, MPH; Gloria Hathaway, PhD Guest Editor: Laura Welch, MD Peer Reviewers: Charles Becker, MD; Jonathan Borak, MD; Joseph Cannella, MD; Bernard Goldstein, MD; Alan Hall, MD; Richard J.Jackson, MD, MPH; Jonathan Rodnick, MD; Linda Rosenstock, MD, MPH; Robert Wheater, MS; Brian Wummer, MD U.S. DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service Agency for Toxic Substances and Disease Registry

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Environmental Medicine: Integrating a Missing Element into Medical Education Case Study Confusion and chest pain in a 67-year-old paint stripper A 67-year-old male patient has been brought by his wife and a neighbor to the hospital emergency room on a weekend while you are on call. Complaining of headache and chest pain, he is unable to provide additional information because of his confusion and disorientation. His wife states that he retired 2 years ago and has been relatively vigorous and in good health since. His principal activities have been house repairs and gardening. He was in his usual state of health, including normal mental alertness for his age, until approximately 2 weeks ago. Over the past 2 weeks, his wife noted progressive loss of mental alertness and increasing fatigue and lethargy, becoming much worse in the evening. He usually sleeps 8 hours a night, but in the past 2 days he has been slow to rise even after 10 hours of sleep. She has noticed that he has become increasingly slow to respond, has slurred speech, and has mood swings from extremely happy to sad or anxious. Yesterday she found him wandering in various rooms of the house and in the yard. Upon questioning, he did not remember why he was in those particular places. He called her a number of times to find tools that he had misplaced, which was unlike him. When she asked him today how he was feeling, for the first time he mentioned having headache and chest pain, but he could not remember when they began. A review of the history provided by his wife reveals that the patient has mild degenerative arthritis in his fingers and hips, for which he takes an over-the-counter variety of ibuprofen. He was evaluated for occasional chest discomfort at age 55, including a treadmill stress test that his wife believes was negative. At that time, a diagnosis for the chest pain was not determined, and the pain resolved without medication. He was hospitalized in his twenties for an appendectomy. He smoked a pack of cigarettes a day from age 20 to age 55, at which time he quit smoking. They have two children and five grandchildren, all alive and well. His parents have been dead for many years; his wife believes that they had some “heart problems.” For the past 2 weeks he has been working, as he has often done in the past, on home repairs and in the garden. He has a basement workshop; his wife knows that he has been preparing some furniture for repainting. She states, “My husband and our neighbor spend many hours on projects and like to be left alone.” She believes that he has been working for approximately 2-hour intervals, removing paint from the furniture. He has also been tending to their lawn; he spread fertilizer once 2 weeks ago, and at least once since then has dusted their roses with what she thinks is a fungicide. The garden materials are stored in their basement. On physical examination, you find a well-nourished, somewhat anxious and disheveled man, appearing his stated age. He is well-tanned and mildly diaphoretic. His blood pressure is 145/80, pulse is 110 and regular, and temperature is normal. He has slurred speech and 15- to 20-second delays in responding to questions. He is oriented only to person, requires concentration for an approximate identification of place, and is disoriented to time. He has little recall of either recent or past events and cannot perform serial numbers. The rest of his physical examination is unremarkable, except for tachycardia with a fourth heart sound. There are no focal neurological findings. An electrocardiogram shows sinus tachycardia and a 1-mm depression of the ST segment in lead V3. A complete blood count, chemistry panel, arterial blood gases, and urinalysis are within normal limits. Upon conferring with the emergency physician, you administer sublingual nitroglycerin during electrocardiographic monitoring. The patient reports relief of chest pain, and the ST segment depression returns to normal. You have him admitted to the coronary care unit for observation. What should be included in this patient’s problem list?________________________________ What is the differential diagnosis for this patient?____________________________________ What tests would you order to confirm or rule out these diagnoses?_______________________ Answers are incorporated in Challenge answers (7) through (9).

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Environmental Medicine: Integrating a Missing Element into Medical Education Exposure Pathways ❑ Because of its high lipid solubility, nonflammability, and high vapor pressure, methylene chloride is used in many important industrial processes and consumer products. ❑ Nonoccupational exposures to methylene chloride occur mainly through hobby and household uses of paint strippers and aerosol sprays. ❑ Principal route of exposure is inhalation. Methylene chloride (dichloromethane) is a clear, colorless liquid with a mild, sweet odor that can be detected at concentrations of 100 to 300 parts per million (ppm). It is neither flammable nor explosive at room temperature. Methylene chloride is also known as DCM, methylene di- (or bi-) chloride. Methylene chloride is lipophilic and is an excellent solvent for many resins, waxes, and fats; it has many industrial applications as a component in aerosol propellants or carrier solvents paint and varnish thinners and removers certain paints and adhesives fire extinguishers and as a process chemical in the manufacture of synthetic fibers photographic film polycarbonate plastics pharmaceuticals printed circuit boards inks Methylene chloride is also used as a blowing agent for urethane foams, an extractant for foods and spices, a grain fumigant, a metal degreaser and cleaner, and a low-pressure refrigerant. Exposures to the highest concentrations of methylene chloride are generally occupational; more than a million workers have significant potential for exposure. Nonoccupational exposures may occur through ambient air or groundwater contaminated by facilities that manufacture, use, store, or dispose of methylene chloride, or from consumer products that contain methylene chloride as a solvent, flame retardant additive, or propellant. The highest nonoccupational exposures probably occur during paint stripping by hobbyists and in the household use of aerosol sprays. Aerosol propellants may contain up to 50% methylene chloride and are commonly used with hair sprays, antiperspirants, air fresheners, and spray paints. Studies have not associated health effects with the low levels of methylene chloride present in decaffeinated coffees and spices after extraction, or with those in chlorinated drinking water. The principal route of human exposure is inhalation. Skin absorption is usually small because of rapid evaporation; however, trapping the liquid against the skin with clothing or gloves can lead to greater absorption and, occasionally, serious chemical burns.

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Environmental Medicine: Integrating a Missing Element into Medical Education (1) The patient’s neighbor remembers similar symptoms in a man with whom he worked during his years as a painter; that coworker had been stripping paint from doors. What does this information suggest? _________________________________________________________________ _________________________________________________________________ (2) In light of (1) above, what specific information would be useful in making a diagnosis? _________________________________________________________________ _________________________________________________________________ _________________________________________________________________ Who’s at Risk ❑ Workers and residents near industrial facilities that produce, use, store, or dispose of methylene chloride have an increased risk of exposure. ❑ Users of certain consumer products may also experience exposure to high levels of methylene chloride for short periods of time. Because the highest exposure levels of methylene chloride occur in the workplace, workers in certain industries (see page 2) are at higher risk of adverse health effects. Persons living near methylene chloride production-and-use facilities or near hazardous waste sites that store methylene chloride may have increased risk of exposure from chemical emissions. Methylene chloride released to the atmosphere readily disperses, so air contaminated by point sources is less of a hazard than contamination of the groundwater. Methylene chloride may remain in groundwater for years and can be widely distributed. From here it may be ingested in drinking water or inhaled as it volatilizes from the water during activities such as showering and laundering.

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Environmental Medicine: Integrating a Missing Element into Medical Education ❑ Persons with preexisting cardiovascular disease may be at increased risk due to methylene chloride exposure. ❑ Carbon monoxide produced by the metabolism of methylene chloride may have adverse consequences on fetal development. In nonindustrial settings, transitory high-level exposures to methylene chloride occur in poorly ventilated areas where adhesives, aerosols, paint strippers, and paint thinners are in use. Exposures to moderately elevated levels of methylene chloride during occasional product use are not expected to cause adverse health effects in normal, healthy persons. Since carbon monoxide is a metabolite (see Biologic Fate), exposure to methylene chloride can produce tissue hypoxia. In persons with coronary artery disease, this may result in angina pectoris or myocardial infarction. Physical exercise during exposure increases the risk to such patients. Persons with already elevated carboxyhemoglobin levels from other sources may also be affected because the metabolism of methylene chloride adds to the total body burden of carbon monoxide. Two common sources of exogenous carbon monoxide are smoking and occupations that involve exposure to exhaust from internal combustion engines. Forklift drivers, diesel mechanics, and tunnel workers, for instance, are susceptible to such exposures. Animal studies have shown that methylene chloride readily crosses the placenta and can enter breast milk. It is not known if the developing human fetus is at increased risk from the direct effects of unmetabolized methylene chloride. Indirect effects from increased levels of maternal carbon monoxide produced by the metabolism of methylene chloride, however, may have adverse consequences on fetal development. (3) Does the patient described in the case study fit the profile of a person at increased risk for adverse effects from methylene chloride exposure? Explain. _________________________________________________________________ _________________________________________________________________ _________________________________________________________________ _________________________________________________________________

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Environmental Medicine: Integrating a Missing Element into Medical Education Biologic Fate ❑ Because of its high lipid solubility, methylene chloride is readily absorbed and quickly distributed throughout the body. ❑ At high levels of exposure, much of the methylene chloride that is inhaled is exhaled unchanged. ❑ At low-level exposures, the primary metabolites of methylene chloride are carbon monoxide and carbon dioxide; at higher levels, formaldehyde and formic acid are also formed. Once methylene chloride has been ingested or inhaled, it is readily absorbed through the lungs and gastrointestinal tract. Dermal exposure also results in absorption, but at a slower rate than other exposure routes. Factors affecting the methylene chloride body burden are exposure level and duration, route of exposure, physical activity, and amount of body fat. In volunteer human subjects, exposures to air levels of 50 to 200 ppm caused the concentration of methylene chloride in the blood to increase linearly with the ambient air concentration. With increasing exposure level, blood saturation occurs and the concentration of methylene chloride in blood reaches a plateau. Following absorption, methylene chloride is distributed mainly to the liver, brain, and subcutaneous adipose tissue. The liver is the primary site of metabolism, although additional transformation occurs in the lungs and kidneys. In the liver, methylene chloride may undergo metabolism by two pathways. The first pathway produces carbon monoxide (CO) and carbon dioxide (CO2) and is saturable at a few hundred ppm. The second pathway yields formaldehyde and formic acid and shows no indication of saturation at inhaled concentrations to 10,000 ppm. The metabolic contribution of each pathway appears to vary in humans, particularly with the exposure level; therefore, toxicity extrapolation between high and low doses is complex. Furthermore, recent studies suggest that the second pathway is considerably more active in certain animal species, particularly mice, a finding that complicates interspecies comparisons. The metabolic formation of carbon monoxide and its subsequent binding to hemoglobin, producing carboxyhemoglobin (CO-Hb), may continue for several hours after cessation of methylene chloride exposure, as fat and other tissues continue to release accumulated amounts of the lipophilic solvent. This endogenous release of methylene chloride, therefore, prolongs the duration of cardiovascular stress to about twice that caused by a comparable CO-Hb level resulting from exposure to exogenous carbon monoxide. The body eliminates methylene chloride primarily through the lungs. A small amount of unchanged methylene chloride is also eliminated in urine and feces. At low doses, a large percentage of methylene chloride is metabolized and eliminated as carbon monoxide, while at higher doses more of the unchanged parent compound is exhaled.

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Environmental Medicine: Integrating a Missing Element into Medical Education (4) Additional information for the case study: You request an inventory of the chemicals in your patient’s workshop. Examination of the materials brought in by the neighbor reveals the following: “ACM”* brand paint stripper, consisting of 80% methylene chloride, 15% mineral spirits, and 5% methanol “Best Bud”* brand rose dust, containing benomyl as the active ingredient “Gro-tall”* brand inorganic fertilizer No insecticides, specifically no organophosphates or carbamates, were found. Explain how the paint stripper might have caused your patient’s cardiac symptoms. _________________________________________________________________ _________________________________________________________________ (5) Could the use of the rose dust or fertilizer be related to your patient’s condition? _________________________________________________________________ *   The use of trade names is for identification only and does not imply endorsement by the Public Health Service or the U.S. Department of Health and Human Services. Physiologic Effects Acute Exposure ❑ The primary effects of inhaled methylene chloride are a result of its narcotic action. The major adverse health effect associated with short-term exposure to methylene chloride at high concentrations is depression of the central nervous system. In some cases with exposure over 8000 ppm, unconsciousness, narcosis, and occasionally death due to respiratory depression have occurred. Lower concentrations (300 to 800 ppm in air) have resulted in impairment of sensory (visual, auditory) and psychomotor functions. The CNS effects are generally reversible and are thought to be due to methylene chloride alone or in combination with metabolically released carbon monoxide, but not to carbon monoxide alone. Other effects of acute exposure include irritation of the eyes and upper respiratory tract, cardiac effects (myocardial ischemia, dysrhythmia) and, very rarely, pulmonary irritation and edema. No substantial human hepatic or renal effects have been reported after an acute exposure to methylene chloride. Skin contact with methylene chloride may cause dermatitis; prolonged skin contact can result in chemical burns. Corneal burns may follow direct eye splashes.

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Environmental Medicine: Integrating a Missing Element into Medical Education Chronic Exposure ❑ Recent evidence suggests that serious long-term effects may result from chronic exposure to methylene chloride. Sequelae of chronic methylene chloride exposures have not been fully determined. Data from epidemiologic studies suggest that there may be serious long-term health effects from chronic exposure to methylene chloride in the form of pancreatic, hepatic, or biliary tract cancer. These occupational data are not sufficient to allow a clear interpretation, however (see Carcinogenic Effects below). Cardiovascular Effects ❑ Persons with coronary artery disease or angina may not be able to tolerate the added cardiovascular stress brought on by carbon monoxide that is metabolically released from methylene chloride. Since exposure to methylene chloride increases the CO-Hb level in the blood, it is expected to have an additive effect on CO-Hb levels produced from other sources. Under normal conditions, the blood contains less than 1% CO-Hb, while a one-pack-a-day smoker will generally have a CO-Hb level of 4% to 5%, and a heavy smoker, 8% to 12%. With exposure to methylene chloride at levels of 500 ppm (the permissible workplace limit) and above, the CO-Hb level has been reported to reach 15% or more in smokers. These CO-Hb levels are below those considered hazardous for most normal, healthy persons but could place additional stress on persons with coronary artery disease or angina. It is well documented that elevation of the CO-Hb level to greater than 2% to 3% saturation can adversely affect such patients. In addition, a recent study of bridge and tunnel workers found an increased incidence of cardiovascular disease, which suggests that long-term, relatively low carbon monoxide exposure may affect cardiovascular risk. Despite animal inhalation studies that suggest exposure to methylene chloride lowers the myocardial threshold to the arrhythmogenic action of injected epinephrine, there is no direct evidence for such an effect in humans. In one study, 24 healthy workers chronically exposed to methylene chloride at concentrations averaging from 60 to 475 ppm were electrocardiographically monitored and showed neither an increase in ventricular or supraventricular ectopic activity nor episodic ST segment depression. Likewise, there was no evidence of cardiac susceptibility or electrographic abnormalities in several case reports of otherwise healthy persons rendered unconscious from acute exposure to methylene chloride. There are no studies that address this arrhythmogenic effect in persons with underlying coronary disease. Hepatic Effects ❑ Methylene chloride has been associated with mild hepatotoxicity in humans. Liver toxicity has not been reported in epidemiologic studies, and it appears that serious hepatic effects would only occur in exposures above current permissible workplace levels. One case of hepatitis and several cases of elevated liver enzymes in exposed workers have been documented. Inhalation studies have demonstrated methylene chloride causes hepatic neoplasms in animals.

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Environmental Medicine: Integrating a Missing Element into Medical Education Carcinogenic Effects ❑ Methylene chloride may be a carcinogenic risk to humans. A long-term (1964–1984) epidemiologic study of workers chronically exposed to methylene chloride during the manufacture of photographic products reported no statistically significant excesses in deaths from lung or liver cancer or from ischemic heart disease. The investigators did, however, report an increased incidence of pancreatic cancer deaths (8 compared with 3.1 expected; median latency 30 years). A more recent epidemiologic study of employees in a fiber production plant has reported an excess of liver and biliary tract cancer deaths among methylene chloride-exposed workers. In both studies, however, the data are not adequate to draw a firm conclusion. Risk of developing cancer from chronic methylene chloride exposure cannot be ruled out. Methylene chloride has been reported to produce benign mammary tumors and malignant liver and lung neoplasms in several animal species. The metabolic pathway in at least one species of these animals is known to be different from that in humans. Nevertheless, on the weight of the evidence, EPA considers methylene chloride a probable human carcinogen. Reproductive and Developmental Effects ❑ Methylene chloride itself does not appear to pose a threat to human reproduction or fetal development. Metabolically released carbon monoxide, however, could be potentially harmful to the developing fetus. No data were found in the available literature on potential reproductive or developmental effects of methylene chloride in humans. Like many other organic solvents, methylene chloride can reach the human fetus through the placenta and can enter human breast milk. Maternal carbon monoxide levels may have an effect on the developing fetus. It has been assumed that the association of low fetal birth weight with mothers who smoke is primarily due to increased levels of maternal carbon monoxide. (6) Could exposure to methylene chloride be the cause of progressive loss of mental acuity, increasing fatigue, lethargy, slurred speech, and mood swings in the patient described in the case study? Explain. _________________________________________________________________ _________________________________________________________________ _________________________________________________________________

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Environmental Medicine: Integrating a Missing Element into Medical Education Clinical Evaluation History and Physical Examination ❑ Assessment of methylene chloride-exposed persons should include evaluation of the CNS, cardiovascular system, pancreas, and liver. A medical history and physical examination are the first steps in evaluating those exposed to methylene chloride. The medical history should include items known to reflect methylene chloride exposure; the physical examination should include evaluation of the central nervous and cardiovascular systems, pancreas, and liver. The medical history should emphasize the following: family history, particularly coronary artery disease occupational history hobbies or household projects, particularly furniture refinishing, spray painting, paint stripping location of residence and workplace in relation to industrial facilities source of drinking water supply Signs and Symptoms Acute Exposure ❑ Signs and symptoms of acute methylene chloride toxicity are generally those due to CNS depression. Methylene chloride exposures at levels below the odor threshold for up to 8 hours have produced no adverse health effects in humans. At levels of exposure at or above the odor threshold, reported effects include the following: euphoria sluggishness light-headedness irritability sleepiness dizziness At exposure levels above 500 ppm, the following may also be present: headache impairment of concentration and coordination loss of balance irritation of eyes, nose, and throat nausea flushing confusion slurred speech ischemic heart pain respiratory distress or failure to maintain the airway during CNS depression pulmonary edema (rare)

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Environmental Medicine: Integrating a Missing Element into Medical Education Table 1 represents a compilation of data from case reports in the literature and summarizes reported symptoms with accompanying exposure levels and duration. At exposure levels over 8000 ppm, unconsciousness has been reported; levels over 50,000 ppm have been reported to be immediately life-threatening. Delayed CNS effects could occur after recovery from severe poisoning. Table 1. Human symptoms and potential airborne concentrations Effect Concentration Exposure Duration ACGIH* TLV† 50 ppm 8 hours Odor threshold 100–300 ppm On exposure OSHA* PEL§ 500 ppm 8 hours No acute effects 100–280 ppm Up to 7.5 hours Altered responses on sensory and psychomotor tests 300–800 ppm At least 40 minutes Light-headedness 500–1000 ppm 1 to 2 hours Irritation, dizziness 2300 ppm 5 minutes Nausea 2300 ppm 30 minutes Headache, fatigue, irritation Up to 5000 ppm Time of onset not specified (noted during 2-year average occupational exposure) Paresthesia, irritation 7200 ppm 8 minutes Narcosis 8000–20,000 ppm 30 minutes to 4 hours Immediately dangerous to life or health >50,000 ppm Immediate *ACGIH=American Conference of Governmental Industrial Hygienists; OSHA=Occupational Safety and Health Administration †TLV (Threshold Limit Value)=the time-weighted average concentration for a normal 8-hour workday and 40-hour workweek, to which nearly all workers may be repeatedly exposed. §PEL (Permissible Exposure Limit)=highest level of methylene chloride in air, averaged over an 8-hour workday, to which a worker may be exposed. Adapted from A.H.Hall and B.H.Rumack, presentation at the American Association of Poison Control Centers/ American Academy of Clinical Toxicology/American Board of Medical Toxicology/Canadian Association of Poison Control Centres Annual Scientific Meeting, Baltimore, MD, October 1–4, 1988. Chronic Exposure ❑ Early signs of chronic methylene chloride exposure are likely to be similar to those of acute exposure. Early signs and symptoms of chronic methylene chloride exposure are not well documented, but are likely to reflect CNS depression. The following have been reported by workers with repeated exposure: headache, dizziness, nausea, memory loss, paresthesias in hands and feet, mental and physical fatigue, and loss of consciousness. In persons with preexisting coronary artery disease or angina, signs and symptoms of angina pectoris and myocardial ischemia may occur.

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Environmental Medicine: Integrating a Missing Element into Medical Education Laboratory Tests Biologic monitoring of chronically exposed workers is often based on direct indicators such as methylene chloride in breath, blood, or urine samples. Monitoring of carboxyhemoglobin levels and liver function tests can also be used. A panel of tests that may aid in evaluating the health of a patient with methylene chloride exposure is presented below. Standard Tests Carboxyhemoglobin level Arterial blood gases Electrolyte panel CBC Hepatic enzyme levels (SGOT or AST, SGPT or ALT) Urinalysis Creatinine Cardiac evaluation (cardiac enzymes and serial electrocardiograms) Specialized Tests Methylene chloride levels in breath, blood, or urine (if exposure is recent) Direct Biologic Indicators ❑ Methylene chloride can be assayed in breath, blood, or urine. ❑ Carboxyhemoglobin and the metabolite formic acid can be measured in blood and urine, respectively. Methylene chloride can be detected in exhaled breath up to several hours postexposure. Breathing ambient levels of 200 ppm methylene chloride will result in about 80 ppm in expired air. The methylene chloride concentration in exhaled air will generally reflect the amount inhaled at ambient levels up to about 500 ppm. The concentration of carbon monoxide in alveolar air also has been found to correlate with methylene chloride levels in ambient air up to 200 ppm. Methylene chloride can be directly measured in the blood shortly after exposure. Of the methylene chloride absorbed, 25% to 90% is eliminated within 2 hours after exposure; 16 hours after exposure, none will be detected in the blood. Interpretation of methylene chloride blood levels is difficult. Workers exposed to currently permissible concentrations usually have blood levels of 1 to 2 µg/mL. There are only a few blood levels reported in the literature, and these are for patients with either fatal or serious poisonings, allowing little comparison. Carboxyhemoglobin, which forms as a result of methylene chloride metabolizing to carbon monoxide, can be detected in blood of nonsmokers about 30 minutes after methylene chloride exposure.

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Environmental Medicine: Integrating a Missing Element into Medical Education Ambient air concentration of approximately 200 ppm of methylene chloride corresponds to carboxyhemoglobin levels of 4% to 9%, similar to levels found in smokers. Exposure to about 500 ppm for several hours results in CO-Hb levels as high as 15%. Since many factors can contribute to elevated CO-Hb levels, including exercise, smoking, and exogenous exposure to carbon monoxide, the CO-Hb level may not correspond directly to inhaled levels of methylene chloride. Urinary levels of formic acid, an intermediate product in the metabolism of methylene chloride, have been used to monitor exposed workers. Indirect Biologic Indicators ❑ There is currently no known indirect biologic indicator that correlates with methylene chloride exposure. Other than CNS effects, short-term, moderate-level exposures to methylene chloride do not appear to cause any measurable changes in biologic parameters. Possible long-term effects include hepatic function abnormalities. (7) You find that the patient described in the case study is suffering from mental confusion. What are some likely causes of this condition in the elderly? _________________________________________________________________ _________________________________________________________________ (8) Initially, you ordered a chemistry panel, CBC, and arterial blood gas tests, the results of which are within normal limits. How do these findings help in your diagnosis? _________________________________________________________________ _________________________________________________________________ (9) The status of subsequent laboratory tests follows. How do you interpret this information? Blood CO-Hb level at least 4 hours after last exposure is 15% Blood methylene chloride level will be available in 1 week Liver function test results are consistent with mild hepatocellular dysfunction CPK isoenzymes, cardiac enzymes, and serial ECGs appear normal _________________________________________________________________ _________________________________________________________________ _________________________________________________________________

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Environmental Medicine: Integrating a Missing Element into Medical Education Treatment and Management Acute Exposure ❑ Life-sustaining procedures and supportive care are the only known treatments for those acutely exposed to methylene chloride. To treat acute toxic exposures, immediately remove the person from the source of exposure and give oxygen or artificial respiration, if indicated. Contaminated clothes should be removed and the exposed skin washed with soap and water. Symptomatic eye exposure requires saline irrigation and inspection for corneal damage. In cases of ingestion, the efficacy of syrup of ipecac, lavage, charcoal, or cathartics is not known. Acute toxic effects may persist for hours after removal from the source of exposure because of continued metabolism of methylene chloride released from tissue storage. Carboxyhemoglobin levels can continue to rise, peaking 5 to 6 hours after exposure. Peak levels have been generally reported to be as high as 25%. Oxygen is the primary therapy. The half-life of CO-Hb in room air is 5.3 hours but this can be reduced to 60 to 90 minutes in 100% oxygen. At high CO-Hb levels, hyperbaric oxygen will reduce the half-life to 20 to 40 minutes. The use of steroids and mannitol for cerebral edema has been recommended, but their value in preventing late neurologic sequelae remains unproven. Because of possible cardiovascular involvement, monitoring for dysrhythmias is indicated. Baseline liver function tests with periodic monitoring to detect possible hepatic toxicity should be performed. Proper use of paint strippers and other methylene chloride-containing products should be discussed with patients. The importance of adequate ventilation or respiratory protection and other protective equipment while using these products should be explained. It would also be prudent to advise patients with coronary artery disease or angina to avoid all exposure to such products. Chronic Exposure ❑ Patients chronically exposed to methylene chloride should be treated symptomatically. There are no known antidotes to methylene chloride and no methods for enhancing the direct elimination of methylene chloride from the body. Most CNS effects due to short-term chronic exposure will resolve when the patient is permanently removed from the source of exposure. If the CO-Hb level is significantly elevated, then the patient should be treated by administering oxygen, as discussed above. Evidence for the usefulness of tests to determine long-term CNS injury, including psychological and neurologic studies, is conflicting.

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Environmental Medicine: Integrating a Missing Element into Medical Education (10) What is the treatment for methylene chloride intoxication? _________________________________________________________________ _________________________________________________________________ (11) What is the prognosis for the patient described in the case study? _________________________________________________________________ _________________________________________________________________ Standards and Regulations Table 2 (page 15) summarizes the standards and regulations for methylene chloride, which are discussed below. Workplace Air ❑ OSHA’s permissible exposure limit is currently under review. The Occupational Safety and Health Administration (OSHA) established a time-weighted average (TWA) standard of 500 ppm (8-hour workday, 40-hour workweek) to prevent acute narcosis and liver injury. In 1986, OSHA issued a notice of proposed rulemaking to lower this standard; to date, no official action has been taken. In 1976, the National Institute for Occupational Safety and Health (NIOSH) recommended a threshold limit value (TLV) of 75 ppm on the basis of an acceptable CO-Hb level of 5% or less at the end of an 8-hour shift. Today, NIOSH considers methylene chloride to be a possible human carcinogen and recommends the “lowest feasible limit” of exposure. The American Conference of Governmental Industrial Hygienists (ACGIH) has recommended that its TLV-TWA of 100 ppm, first proposed in 1981, be lowered to 50 ppm. The new ACGIH guideline is designed to reduce carcinogenic risk and avoid excessive levels of CO-Hb.

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Environmental Medicine: Integrating a Missing Element into Medical Education Table 2. Standards and regulations for methylene chloride Agency* Focus Level Comments ACGIH Air-Workplace 50 ppm Advisory; TWA†; to avoid carcinogenic risk NIOSH Air-Workplace N/A Advisory; lowest feasible level OSHA Air-Workplace 500 ppm Regulation; PEL§ as TWA† EPA Air-Environment N/A Under review; proposal scheduled for June, 1990 FDA Cosmetics 0 Regulation; ban became effective in 1989   Food 10 ppm Regulation; residual in decaffeinated coffee *ACGIH=American Conference of Governmental Industrial Hygienists; EPA=Environmental Protection Agency; FDA=Food and Drug Administration; NIOSH=National Institute for Occupational Safety and Health; OSHA=Occupational Safety and Health Administration †TWA (Time-Weighted Average)=time-weighted average concentration for a normal 8-hour workday and a 40-hour workweek to which nearly all workers may be repeatedly exposed. §PEL (Permissible Exposure Limit)=highest level of methylene chloride in air, averaged over a normal workday, to which a worker may be exposed. Environment Air ❑ EPA has not promulgated an emission standard for methylene chloride. The Office of Toxic Substances (OTS) within EPA promulgates regulations related to manufacturers and processors of chemicals that may present an unreasonable risk to health or the environment. The OTS has initiated a priority review of human cancer risks from certain exposures to methylene chloride; no regulation has emerged to date.

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Environmental Medicine: Integrating a Missing Element into Medical Education Water ❑ EPA currently has no standard regulating the amount of methylene chloride in public drinking water supplies. The EPA Office of Drinking Water projects that a standard for methylene chloride will be proposed in June 1990. Food ❑ FDA has banned the use of methylene chloride in cosmetics. The Food and Drug Administration (FDA) has recently reviewed the risks to humans of exposure to methylene chloride. The outcome was a ban on the use of this chemical as an ingredient of cosmetic products. The FDA continues to permit the use of methylene chloride as an extraction solvent for decaffeinating coffee, with an allowable residual concentration up to 10 ppm in the decaffeinated coffee. Other ❑ CPSC is reviewing the use of methylene chloride in consumer products. The use of methylene chloride in spray paints and paint strippers for household use is under review by the Consumer Product Safety Commission (CPSC). Suggested Reading List General Andersen ME, Clewell HJ III, Gargas ML, Smith FA, Reitz RH. Physiologically based pharmacokinetics and the risk assessment process for methylene chloride. Toxicol Appl Pharmacol 1987;87:185–205. DiVincenzo GD, Kaplan CJ. Uptake, metabolism, and elimination of methylene chloride vapor by humans. Toxicol Appl Pharmacol 1981;59:130–40. Ott MG, Skory LK, Holder BB, Bronson JM, Williams PR. Health evaluation of employees occupationally exposed to methylene chloride. Scand J Work Environ Health 1983; Suppl 1:1–38. Stewart RD, Fisher TN, Hosko MJ, Peterson JE, Baretta ED, Dodd HC. Experimental human exposure to methylene chloride. Arch Environ Health 1972;25:342–8. Carboxyhemoglobin Anderson EW, Andelman RJ, Strauck JM, Fortuin NJ, Knelson JH. Effect of low-level carbon monoxide exposure on onset and duration of angina pectoris: a study in ten patients with ischemic heart disease. Ann Intern Med 1973;79:46–50. Atkins EH, Baker EL. Exacerbation of coronary artery disease by occupational carbon monoxide exposure: a report of two fatalities and a review of the literature. Am J Ind Med 1985;7:73–9. Hall AH, Rumack BH. Methylene chloride exposure in furniture-stripping shops: ventilation and respirator use practices. J Occup Med 1990;32:33–7. Ratney RS, Wegman DH, Elkins HB. In vivo conversion of methylene chloride to carbon monoxide. Arch Environ Health 1974;28:223–6. Stewart RD, Fisher TN, Hosko MJ, Peterson JE, Baretta ED, Dodd HC. Carboxyhaemoglobin elevation after exposure to dichloromethane. Science 1972;176:295–6.

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Environmental Medicine: Integrating a Missing Element into Medical Education Pancreas Hearne FT, Grose F, Pifer JW, Friedlander BR, Raleigh RL. Methylene chloride mortality study: dose-response characterization and animal model comparison. J Occup Med 1987;29:217–28. Mack TM. Pancreas. In: Schottenfeld D, Fraumeni JF Jr, eds. Cancer epidemiology and prevention. Philadelphia: WB Saunders Co, 1982:638–67. Liver Puurunen J, Sotaniemi E. Usefulness of follow-up liver-function tests after dichloromethane exposure. Lancet 1985;1:822. Neurologic Barrowcliff DF, Knell AJ. Cerebral damage due to endogenous chronic carbon monoxide poisoning caused by exposure to methylene chloride. J Soc Occup Med 1979;29:12–4. Cherry N, Venables H, Waldron HA, Wells GG. Some observations on workers exposed to methylene chloride. Br J Ind Med 1981;38:351–5. Paint-Remover Hazard Langehennig PL, Seeler RA, Berman E. Paint removers and carboxyhemoglobin. N Engl J Med 1976;295:1137. Stewart RD, Hake CL. Paint-remover hazard. JAMA 1976;235:398–401. Related Government Documents Agency for Toxic Substances and Disease Registry. Toxicological profile for methylene chloride. Atlanta: US Department of Health and Human Services, Public Health Service, 1989. NTIS report no. PB/89/194468/AS. Centers for Disease Control. Criteria for a recommended standard. Occupational exposure to methylene chloride. Atlanta: US Department of Health and Human Services, Public Health Service, 1976. USDHHS report no. (NIOSH) 76–138; NTIS report no. PB81–227027. Centers for Disease Control. Current intelligence bulletin 46: methylene chloride. Atlanta: US Department of Health and Human Services, Public Health Service, 1986. USDHHS report no. (NIOSH) 86–114. Environmental Protection Agency. Addendum to the health assessment document for dichloromethane (methylene chloride): final report. Washington DC: US Environmental Protection Agency, Office of Health and Environmental Assessment, 1985. Report no. EPA/600/8–82/004FF.

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Environmental Medicine: Integrating a Missing Element into Medical Education Answers to Pretest and Questions Pretest is on page 1. Challenge questions begin on page 3. Since both your patient and the former coworker described by the neighbor were removing paint from wood, it is reasonable to suspect the product used for that purpose could have caused the symptoms noted. You could ask your patient’s wife or neighbor to examine the contents of the workshop, and bring in the labels or containers of any materials that the patient may have used over the past 2 weeks. Even if inconvenient, it can be more productive to have someone inspect the patient’s environment, rather than relying on laboratory tests. You could also ask a public health official to examine the patient’s workshop. To the extent the patient’s history and risk factors indicate possible coronary artery disease or angina, he would fit the profile of one at increased risk from methylene chloride exposure. Methylene chloride constitutes 80% of the paint stripper, and because of its high volatility, could reach a significant ambient level in a poorly ventilated area such as a basement workshop. Methylene chloride is metabolized in part to carbon monoxide, sometimes producing elevated carboxyhemoglobin (CO-Hb) levels when overexposure occurs. Continued production of CO-Hb during gradual release of methylene chloride from adipose tissue may lead to prolonged tissue hypoxia, resulting in cardiac ischemia, particularly when coronary artery disease is already present. The other constituents of the paint stripper, mineral spirits and methanol, are also anesthetic agents, but in these concentrations have likely contributed only slightly to your patient’s mental confusion. No. It is unlikely that the rose dust or fertilizer contributed to your patient’s symptoms. The fertilizer is an inorganic material that could cause eye, nose, or throat irritation, but when applied in the normal fashion, has no other toxic effects. Benomyl is a fungicide of extremely low acute toxicity. Yes. Methylene chloride is a general anesthetic (central nervous system depressant). The patient’s mental condition is of subacute onset and duration and is consistent with overexposure to an organic solvent such as methylene chloride. Besides cardiac ischemia, your patient’s problem list includes a mentally confused state that may be classified as either delirium or dementia. The distinguishing factors between these two conditions are (a) onset and duration and (b) state of consciousness. Delirium has a more acute onset and shorter duration (lasting several hours to days) and is characterized by a variable clouding of consciousness, usually worsening at night. Such states are not uncommon in the elderly. It is important when confronted with such a patient that the physician look for a treatable cause. The existing laboratory findings rule out electrolyte and glucose disturbances or hypoxemia as a cause of the observed encephalopathy. Elevated CO-Hb levels in a nonsmoker, in the absence of exogenous carbon monoxide exposure, is strongly suggestive of exposure to methylene chloride. A methylene chloride blood level, when available, can be used to confirm the presence of the chemical. Methylene chloride is mildly toxic to the liver. Liver function tests should be performed and could be used to rule out liver failure as a cause of dementia. Normal cardiac enzymes and serial ECGs indicate the patient did not have a myocardial infarction. There is no antidote or specific treatment for methylene chloride intoxication per se. The administration of oxygen will increase the dissociation of carbon monoxide from hemoglobin and thereby hasten the elimination of CO-Hb. Oxygen will also alleviate the tissue hypoxia. Most persons will recover from the acute and subacute effects of organic solvents on the central nervous system. Assuming there is no hypoxic tissue damage, your patient should also recover completely. Persons with long-term chronic exposure, such as painters and solvent abusers, may experience permanent neurobehavioral dysfunction, specifically, memory deficits and vestibular or cerebellar damage.