Document 7Ro4XqG4Vdy0BoJg8NzVZ654g

9 4 4 TSDR cut v TO* APR 1 m 1991 M. C* LEVVJAISOHJV VtNyL. G4u)iD' June igg0 Case Studies in Bivironmental Medicine Vinyl Chloride Toxicity __StuMnoHmeHtol ALERT . . . El 0 Chronic, low-level vinyl chloride exposure may cause angiosarcoma of the liver, an extremely rare form of cancer. At higher doses, hepatic cells may die rather than transform, which results in chronic liver disease. m Hepatic angiosarcoma has not been reported in workers who were exposed m to vinyl chloride after 1974, when permissible workplace air levels were drastically reduced. Thisfinding, however, may reflect an incomplete latency period. This monograph is one in a series ofself-instructionalpublicationsdesignedto increase theprimarycareprovider's knowledge of hazardous substances in the environment and to aid in the evaluation of potentially exposed patients. The Agency for Toxic Substances and Disease Registry (ATSDR) and the Centers for Disease Control (CDC) designate this continuing medical education activity for 1 credit hourin Category 1 ofthe Physician's Rec ognition Award of the American Medical Association and 0.1 continuing education units for other health professionals. See pages 19 to 21 for further information. Quest Contributors: Robert Harrison, MO, MPH; Gloria Hathaway, PhD Quest Editors: Laura Welch, MD; Carlo Tamburro, MD Peer Reviewers: Charles Becker, MO; Jonathan Borak, MD; Joseph Cannelta, MD; Bernard Goldstein, MD; Alan Had, 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 ^ 060746 TSDR How to use this Issue... This issue begins with a composite case study that describes a realistic encounterwith a patient. This description is followed by a pretest. The case study is further developed through Challenge questions at the end of each section. To fully benefit from this monograph, readers are urged to answer each question when it is presented. (Answers to the Pretest and Challenge questions are found on pages 17-18.) The monograph endswith a posttest, which can be submitted to ATSDR for continuing medical education (CME) credit or continuing education units (CEU). See page 19 for further instructions on how to receive these credits. The objective of this monograph on vinyl chloride Is to help you: Understand why vinyl chloride remains a hazard of great concern Understand the Known factors contributing to vinyl chloride poisoning Assess a patient's environmental or occupational exposure to vinyl chloride Effectively evaluate and manage vinyl chloride-exposed patients Utilize a variety of sources to locate further information on vinyl chloride Contents Case Study................................................. 1 Pretest........................................................ 1 Exposure Pathways...................................2 Who's at Risk.............................................3 Biologic Fate..............................................4 Physiologic Effects.....................................5 Clinical Evaluation......................................8 Treatment and Management.................... 13 Standards and Regulations...................... 14 Suggested Reading List........................... 16 Answers to Questions..............................17 Sources of Information............................. 18 Posttest.................................................... 19 This issue is prepared with the assistance of those who share a common concern tor physician education, public health, and the environment, including the following organizations: American Academy of Family Physicians (AAFP), American Academy of Pediatrics (AAP), American College of Emergency Physicians (ACEP), American College of Occupational Medicine (ACOM), American Medical Association (AMA), Association of State and Territorial Health Officials (ASTHO), and the Society of Teachers of Family Meticine (STFM). Final responsibility for the contents and views expressed in this monograph resides with ATSDR. Agency for Toxic Substances and Disease Registry Project Officers: Max Lum, Ed.D., and Donna L Ortl, M.S. Prepared by DeUma Associates, San Rafael, California, under Contract No. 205-88-0636 ucc 060747 Case Study A 55-year-old man with weight loss and hepatomegaly A 55-year-old man seen at your office complains of fatigue, a 20-pound weight loss, and anorexia over the past 2 to 3 months. He has previously been in good health, except for a history of hypertension, for which he has been treated with hydrochlorothiazide, 50 mg a day, for the past 3 years. He takes no other medications, has never had a blood transfusion, and has not travelled outside the United States. He consumes 2 to 3 alcoholic beverages a week and does not smoke tobacco. Questioning reveals that he has been a car salesman for 25 years. He is married, has 3 children, and has lived near an industrial park for the last 18 years. Three and a half years ago, he and his family were evacuated from their home for several days after a railroad tanker car derailed and ruptured on the nearby railroad tracks. He and his family were treated at a local emergency room for sore throat and cough; acute respiratory complaints resolved within 2 weeks. He does not recall the name of the chemical that was released, but he remembers it had a slightly sweet odor, an odor he has occasionally noticedwhile in the backyard. His youngest daughter, who has just turned 19, gave birth to a boy last week; the pregnancy was troubled, but the baby is fine. The rest of his family is in good health. On physical examination, your patient appears to be in poor health. Blood pressure is 140/80; pulse is 72 and regular. He is afebrile. Weight is 174 pounds. There are no skin rashes or lesions. Sclerae are slightly icteric; the remainder of the HEENT examination is normal. There is no thyromegaly or lympfcadenopathy. The results of heart and chest examination are normal. The patient's liver is 14 cm in span, percusses at the middavicular line, and is slightly tender to palpation; the lower border is palpable 4 cm below the costal margin. The spleen is not enlarged, and there are no other abdominal masses. Extremities and joints are unremarkable, and the results of neurologic examination are completely normal. Prostate is normal-sized; no masses are felt, and the stool is negative for occult blood. The initial laboratory results include hemoglobin, white blood cell count, electrolytes, and urinalysis, all normal. The SGPT is 372IU/L and SGOT is 293IU/L. Bilirubin, alkaline phosphatase, and serum protein levels are within normal limits. (a) What should be included in this patients problem list? (b) What is the differential diagnosis for this patient? (c) What tests would you order to confirm or njie out these diagnoses? Answers are incorporated in Challenge answers (6) through (9) on pages 17-18. UCC 060748 TSDR Exposure Pathways Th* sweet odor of vinyl chloride can ba dotactad only at concentration* too high to provlda adaquate warning of toxic levels. Exposures may occur through air polluted with vinyl chloride from processing, polymeriza tion, and fabrication plants or hazardous waste sites, and through groundwater contami nated by these sources. Q Consumer sources of vinyl chlorids may Include release of the monomer from PVC plastic in new car Interiors, packaging of certain foods and beverages, and pipes for drinking water. Vinyl chloride (CH2CHCi) is a manmade chemical with no signifi cant natural source, it is a colorless gas at room temperature but is normally stored under pressure and used as a liquid. It has a mild, sweet odor that can be detected at 300 to 5000 parts per million (ppm), too highto provide adequate warning of danger. Vinyl chloride is soluble in fats and organic solvents and is only slightly soluble in water. Synonyms include chloroethene, monochioroethytene, VC, and VCM (vinyl chloride monomer).Throughout the text, "vinyl chlo ride" refers to the vinyl chloride monomer, unless otherwise stated. The primary use of vinyl chloride is in the production of polyvinyl chloride (PVC), a plasticthat is usedto make pipe, electrical wire and cable coatings, flooring, home furnishings, toys, packaging, apparel, and automobile parts and upholstery. Smaller amounts of vinyl chloride are used as a copolymer in the manufacture of other plastics, as an intermediate in the production of chlorinated com pounds, and as a refrigerant. Historically, vinyl chloride has been used as an aerosol propellant and, at one time, was considered for use as an anesthetic. Normally, the general population is exposed to negRgble amounts of vinyl chloride. Amounts measured in ambient air nearvinyl chloride production plants have been up to 1 ppm and, above hazardous waste sites, up to 0.4 ppm. Other sources of airborne exposure include volatilization from new plastic parts and upholstery in car interiors. Release of residual vinyt chloride monomer from most other solid PVC materials is generally of little consequence, although significant amounts of vinyl chloride may be released during burning of PVC products. Tobacco smoke also contains smal amounts of vinyl chloride. In general, atmospheric environmental levels of vinyl chloride are not injurious and present no known risk. Many consumer goods, including food and beverages, are pack aged in various forms of polyvinyl chloride. Smal amounts of residual vinyl chloride monomer can migrate Mo the packaged contents and be consumed. Residual monomercan alsobe leached into the drinking water supply from new PVC piping. Studies have shown, however, that the amount of vinyl chloride ingested from either of these sources is small. Vinyl chloride released from point sources into the ambient air is degraded in a matter of hours; that released to lakes, streams, or rivers will volatilize in several hours to days, depending on the water's temperature and aeration rate. Vinyl chloride may remain in 2 Ucc 060?<tg groundwater, however, for months or years. Of all potential sources of vinyl chloride exposure to the general population today, contami nated groundwater is the most enduring. The majority of drinking water supplies in the United States contain no detectable amounts of vinyl chloride. Vinyl Chloride Toxicity (1) Additional information for the case study: After checking with the local fire department, youfindthat vinyl chloride was contained ft the overturned tanker car and that there was an airborne release of approximately 10,000 gallons of vinylchloride. Furthermore, you learn from the regionaloffice ofEPA that significant leaks in the reactor vessels of the nearby plant may have been occurring over the course of several decades, resulting in frequent environmental contamination, although no air moni toring had been done outside the plant. After the tanker car accident, the complex permanently closed. What further information will you request in order to evaluate the extent of your patient's exposure? (2) What are the significant sources of vinyl chloride exposure for this patient? Who's at Risk Those at greatest risk of vinyl chloride exposure are the 2.2 million workers concerned with the production, use, transport, storage, and disposal of this material. The highest health risk has been to workers exposed as a result of the polymerization process, especially to those who were lowered directly into the reactor vessels to remove solid polymer adhering to the inside. During this cleaning process, the exposure levels to vinyl chloride monomer were typically in the range of 100 ppm or more. Q Of the 2.2 million workers exposed to vlnyt chloride, autoclave cleaners In PVC production plants have the highest health risk. UCC 060750 3 =AjTSDR Certain persona, such as alcoholics, have an Increased risk of vinyl chloride toxicity. During the childbearing years, women should avoid exposure since there Is a possibility that vinyl chloride Increases the Incidence of congeni tal birth defects. Prenatal or early exposure to vinyl chloride may Increase the risk of cancer later. Data from animal studies suggest that prior exposure to chemicals or drugs that stimulate the enzyme systems involved in vinyl chloride hepatic metabolism may result in increased risk of hepatotoxicity. The formation of scar tissue, which results from vinyl chlorideinduced chronic liver disease, has been reported to cause hepato mas that can become malignant when ethanol is consumed. The fetus may also be at increased risk. One human study suggests that maternal exposure to low ambient levels of vinyl chloride is associated with an increase in the incidence of congenital malforma tions, but these results have not been supported by the findings of at least two subsequent studies. Based on extrapolation of animal data, exposure to vinyl chloride either in the prenatal period or during early childhood years may result in an increased risk of developing cancer. CluUkngt (3) Who in the case study, besides the patient, is at risk of being exposed to vinyl chloride? (4) Do the children of this patient have an increased risk of developing cancer? Does his grandson? Why? Biologic Fate Primary routes of vinyl chlorlda antry In humans art Inhalation and Ingastlon. For vinyl chloride, the primary routes of entry in humans are inhala tion and ingestion. Metabolic pathways are readily saturable, which limits systemic uptake at higher doses. Vinyl chloride that is not metabolized is exhaled. 4 UCC 060751 Vinyl Chloride Toxicity Animal studies indicate that inhalation absorption of vinyl chloride occurs readily and rapidly, but data are insufficient to determine the proportion of an inhaled dose that Is absorbed. Absorption from the gastrointestinal tract is rapid and probably complete, as shown by several studies performed on rats. Evidence suggests that the toxicity of vinyl chloride is related to its transformation in the liver to one or several reactive metabolite(s). Suspected intermediate metabolites, 2-chloroethylene oxide and 2-chloroacetaldehyde, can bind to cellular macromolecules such as DNA and proteins, presumably causing liver damage. These metabolites can also undergo further oxidation to compounds such as 2-chloroacetic acid and thiodiglycolic acid, which are mainly excreted in the urine. Q Following absorption, vinyl chloride Is metabo lized In the liver. The primary metabolites can causs cellular damage or be further metabolized to compounds that are ex creted In the urine. Physiologic Effects Acute Exposure Most data regarding acute inhalation exposure to vinyl chloride are early reports among occupationally exposed workers. Deaths ap peared to be due to narcosis, but no specific exposure levels have been reported. Presumably, these exposure levels exceeded 10,000 ppm. Autopsies revealed congestion of the liver, spleen, and kidneys. With acuta exposure to vinyl chloride, the nerv ous system Is the primary target Chronic Exposure Several epidemiologic studies have convincingly associated chronic vinyl chloride exposure with liver tumors, both malignant and non* malignant, and have suggested, but not proved, an increased inci dence of cancers in other parts of the body. Subtle neurologic effects have been noted In some workers chronically exposed to vinyl chloride. Vinyl chloride exposure also has been associated with decreases in pulmonary flow, interstitial pneumonitis, and "meat packers' asthma." With subacute or chronic exposure, the primary target organ la tha liver. 5 ucc 060752 -VTSDR Vinyl chloride can cause malignant or nonmallgnant liver Injury, depend ing on exposure level. Subtle signs of neurotox icity have recently been associated with chronic exposure to vinyl chlo ride. Vinyl chloride-induced angiosarcoma of the liver has a reported latency of 15 to 40 years. Hepatic Effects Hepatocellular injury of any kind is manifested only after months or years of vinyl chloride exposure. Epidemiologic studies suggest that chronic exposure to very high doses (on the order of 500 to 1000 ppm) leads more often to hepatotoxicity, while exposure to lower doses (100 ppm or less) results more often in carcinogenicity. At the higher levels hepatic cells often die rather than transform, which results in chronic liver disease. Hepatic angiosarcoma is a multicentric lesion that typically occupies peripheral foci within the liver. The highly vascular nature of angio sarcomas causes the bruits and may result in massive peritoneal hemorrhage. Nonmalignant hepatic manifestations of vinyl chloride exposure include noncirrhotic portal hypertension and cirrhosis, depending on the nature of exposure. In cases of acute exposure, the resulting chemical hepatitis rarely progresses into fulminant hepatic necrosis. Chronic exposure results in periportal fibrosis without portal vein obstruction, collagen deposition in the space of Disse, and hyperplasia of the mesenchymal sinusoidal lining cells, which ultimately become fibrotic. Vinyl chloride exposure should be considered before the diagnosis of idiopathic portal hypertension is made. Exposure to arsenic, thorium, and copper may also cause portal hypertension without cirrhosis. Findings of capsular and subcapsular fibrosis are suggestive but not diagnostic of vinyl chloride exposure. Neurologic Effects Vinyl chloride was once considered for use as an inhalation anes thetic agent, a result of its central nervous system effects at subacute exposures. Recent data suggest that more subtle signs of neurotox icity can be associated with chronic exposure. Peripheral neuro pathy of the legs has been reported in workers exposed to vinyl chloride at levels lessthan 50 ppm. Electroencephalographic changes have been noted in workers chronically exposed to vinyl chloride at high levels and in combination with other organic solvents. Further investigation in this area is needed. Carcinogenic Effects Numerous epidemiologic and experimental studies have indicated the carcinogenic potential of vinyl chloride. A worldwide register of histologically confirmed cases of hepatic angiosarcoma resulting from vinyl chloride exposure identified120 cases from 1974 to 1986; additional cases are now being added at the rate of about 5 a year. 6 ucc 060753 Most of these cases were found 15 to 29 years after first exposure; the mean age of patients at diagnosis was 52 years, and the aver age length of exposure was 18.3 years. As of 1986, at least 43% (53/120) of the people with this rare form of cancer were employed as reactor cleaners; exposure levels then were presumably much greater than those seen today. Most of the workplace cases of vinyl chloride-induced hepatic angiosarcoma have been associated with chronic exposures on the order of 100 ppm or less; evidence for increased incidence of disease below 50 ppm has not been clearly documented in human studies. There have been no cases of hepatic angiosarcoma recorded in workers due to vinyl chloride exposure after 1974, when allowable workplace air levels were drastically reduced. However, a sufficient latency period has not yet elapsed for carcinogenic effects to have appeared. Data on the few cases of hepatic angiosarcoma report edly due to environmental contamination are inconclusive because of the statistically small numbers involved and because this disease can arise spontaneously. Increased incidence of several cancers, other than hepatic, have been suggested by various epidemiologic studies of vinyl chlorideexposed workers and by animal studies. Presently, there is insuffi cient evidence to establish a causal relationship in humans between environmental vinyl chloride exposures and suggested increased incidences of cancer of the brain, breast, skin, lung, thyroid, lym phatic, or hematopoietic tissues. Increased frequencies of chromosomal aberrations in circulating peripheral lymphocytes, including fragments, rings, breaks, and gaps, have been reported in vinyl chloride workers. In general, these aberrations have not been associated with exposure to vinyl chloride levels less than 5 ppm. Studies using a number of biologic assay systems suggest that the reported carcinogenicity of vinyl chloride may proceed by damage to the cell's genetic material. Vinyl Chloride Toxicity (5) Wouldyou examine the patientdesorbedin the case study tor CNS damage? Formalignancies other than hepatic? Explain. 7 ucc 060754 TSDR Clinical Evaluation Th* onMt of symptom* dus to chronic vinyl chloride exposure may b* delayed for several years after the actual exposure has ceased. History and Physical Examination A detailed occupational history should include any past exposure to vinyl chloride. The latency period for nonmalignant complications may be several months, while the latency period for angiosarcoma of the liver may be as long as 40 years. Workers exposed before 1974, when permissible workplace levels were still high, are at increased risk for the development of hepatic angiosarcoma into the next century. Individual susceptibility as well as intensity andduration of exposure may affect the interval before symptoms are manifested. Persons who have been chronically exposed to vinyl chloride are likely to have worked or lived in locations where the chemical was produced, used, or stored. Such proximity to vinyl chloride plants op erating before 1960, when engineering controls were inadequate, is particularly suspect. Although the number of symptomatic persons having this type of exposure is small, angiosarcoma of the liver is so rare that the incidence of everyone case near such a plant may be initially regarded as evidence of environmental pollution. Documen tation of environmental contamination, in airor drinking water, would suggest a need to monitor other potentially exposed members of the community, past and present residents, and workers connected with the source of exposure. Two other chemical agents have been specifically associated with angiosarcoma of the liver, and exposure to them should be ruled out by history; these are inorganic arsenic and thorium dioxide (a com ponent of the X-ray contrast medium Thorotrast). Anabolic and con traceptive steroids have also been associated with the induction of hepatic angiosarcoma, and their use should be determined. In ad dition to alcohol consumption and smoking habits, any medications that normally or adversely affect the liver should be noted. The possible use of homeopathic medications and so-called health foods should be investigated. The physical examination for vinyl chloride-exposed persons in cludes a thorough abdominal and neurologic examination. The ex tremities of vinyl chloride workers, particularly the hands, should be examined for signs of acro-osteoiysis, a result of "vinyl chloride disease,' discussed in Signs and Symptoms section. ucc a 060755 Vinyl Chloride Toxicity Signs and Symptoms Acute Exposure Vinyl chloride has little acute toxicity, and air levels over 8000 ppm may be tolerated for 5 minutes without the development of symp toms. Longer exposures have been associated with headache, dizziness, euphoria, ataxia, and narcosis. Cardiac, circulatory, and respiratory irregularities have also been noted with acute exposures. Acute, high-level exposures have resulted in death, presumably due to narcosis. Short-term vinyl chloride exposure at relatively high concentrations may be tolerated without lasting adverse effects. Chronic Exposure Chronic occupational exposures to vinyl chloride at levels of several hundred ppm have led, in the past, to vinyl chloride disease, a con dition involving a numberof organ systems and tissues and resulting in a variety of clinical symptoms. The reported period of exposure before the onset of this disease ranged from 1 month to 3 years. New cases of vinyl chloride disease have not been reported since 1974, when permissible workplace exposure levels were reduced to 1 ppm. The signs of vinyl chloride disease included a scleroderma-like condition of the connective tissue of the fingers, accompanied by thickening of the dermis. Acro-osteolysis, a rare bone disease re sulting in decalcification of the terminal phalanges of the hand, was also seen. Acro-osteolysis was frequently p receded by a Raynaudtype phenomenon in which there was reversible constriction of the arterioles, leading to numbness, pallor, and cyanosis of the fingers. The onset of vinyl chloride-induced liver disease (malignant or non* malignant) can be insidious, with a clinical picture of nonspecific hepatic injury. Abdominal pain, followed by weakness, fatigue, and weight loss are the most common symptoms. Fibrosis and cirrhosis may develop, resulting in hepatomegaly, splenomegaly, portal hy pertension, thrombocytopenia, and esophageal varices. These pathologic effects may occur singly or in any combination and may be accompanied by other less characteristic signs, such as hematol ogic changes and pulmonary effects. Vinyl chloride disease appears to be a disease of the past. The onset of vinyl chloride-induced liver damage Is Insidious, with a clinical picture of non specific hepatic Injury. UCC 060756 9 TSDR In the evaluation of vinyl chlorlda-axposad patients. It Is Important to exclude other etiologies for liver disease. There Is no reliable direct Indicator for vinyl chloride exposure at low levels. 10 Laboratory Tests Short of liver biopsy, there are no definitive clinical clues to distin guish hepatic injury due to vinyl chloride from that of other etiologies such as viral hepatitis infection and ethanol toxicity. (Vitamin A overload, hemochromotosis, andcarbontetrachloride exposure have been reported to cause liver disease only rarely.) Biliary cirrhosis, cholelithiasis, and metastatic cancer should also be considered in the differential diagnosis of liver injury. Laboratory tests can be used to evaluate patient health, confirm vinyl chloride exposure, and exclude other etiologies such as hepatitis virus.Tests that may be helpful are listed below. Since the histologic appearance of vinyl chloride-induced liver injury is distinct from that due to other agents, biopsy may be the best method to diagnose liver disease caused by this chemical. Screening Tests Urinary coproporphyrin and total urinary porphyrins Liver enzymes Liver function tests (see below) Serum bilirubin CBO with peripheral smear BUN and creatinine Urinalysis Hepatitis serology Specialized Tests Vinyl chloride in breath or urine, if exposure is recent Urinaiy thiodiglycolic acid, V exposure is recent Direct Biologic Indicators No reliable direct method exists for biologically monitoring exposure to low levels of vinyl chloride. Attempts have been made to correlate vinyl chloride exposure with urinary output of thiodiglycolic acid, a major urinary metabolite that peaks approximately 20 hours after exposure. Because of wide individual variations in excretion pat terns, however, urinary thiodiglycolic acid is not reliable when exposure to vinyl chloride occurs at concentrations less than 5 ppm nor several days after exposure. Likewise, at air concentrations less than 5 ppm, no correlation has been found between the amount of vinyl chloride in breath or urine samples and the concentration in inspired air. C ' --t UCC 060757 Vinyl Chloride Toxicity Indirect Biologic Indicators Overt liver injury is a relatively late occurrence in vinyl chloride-re lated hepatic disease, and detection of early chemical injury in asymptomatic persons is difficult. Standard biochemical enzyme studies (alkaline phosphatase, aspartate aminotransferase [SGOT or AST], alanine aminotransferase [SGPT or ALT] and gamma-glu tamyl transpeptidase [GGTP or GGT]), when used alone, are of lim ited value in identifying the early phases or progression of liver injury. These enzymes primarily reflect acute disruption in cell membrane integrity rather than alterations in the uptake, metabolism, storage, or excretion functions of hepatic cells. Furthermore, these enzyme levels may be elevated in nonhepatic diseases or may return to normal after initial elevation in subacute, chronic, or end-stage liver disease, thus complicating their interpretation. A correlation has been noted between slightly to moderately ele vated total urinary porphyrins or secondary urinary coproporphyrin and the early stages of toxic liver disease. However, no similar observations have been reported in patients with vinyl chloriderelated liver disease. Recent studies have suggested that measuring clearance rates of substances removed from the circulation by the liver provides the most sensitive and specific indicator of earfy chemically induced liver injury. Indocyanine green (ICG) is a synthetic dye used for this purpose, and ICG clearance rates are directly related to the severity of chemical hepatic injury. This test, however, has certain limitations: it is invasive, involves intravenous injection of a synthetic dye, ne cessitates drawing multiple blood samples with same-day analysis, and is fairly expensive. Serum bile acids are also cleared by the liver; measurement requires drawing a single fasting serum sample to obtain levels, usually by ra dioimmunoassay. These bile acids, cholylglycine and conjugates of cholic acid, have been shown to be significantly elevated in asymp tomatic workers with chemical exposure and histologically proven chemical liver injury. A screening panel of fasting serum bile acids and liver enzyme assays or ICG clearance rates is both sensitive (few false negatives) and specific (few false positives) for chemically induced hepatic injury. In asymptomatic persons, the presence of elevated liver Except in an ongoing medical surveillance program, standard bio chemical and liver func tion tests alone may be f limited value In evaluating vinyl chloride-induced liver injury. a A rise In urinary coproporphyrin and total uri nary porphyrins can signal the early stages of hepatocellular disease. Recent studies suggest that fasting serum bile acids, In conjunction with an indocyanine green clearance rate, are sensi tive and specific for latent chemical liver injury. 11 ucc 060758 TSDR ( enzymes or abnormal ICG clearance rates, in conjunction with normal bile acids, is characteristic of hepatic cellular injury due to alcohol, drugs, or viral hepatitis. On the other hand, elevated tasting serum bile acids, in conjunction with persistent enzyme abnormali ties or elevated ICG clearance rates, are more indicative of subclinical hepatic injury due to low-grade chemical exposure. When serum bile acids, alkaline phosphatase, and SGPT (ALT) are all normal, there is a high probability of excluding latent liver disease due to any cause; only a liver biopsy is more definitive. (6) What should be included in the problem list for the patient described in the case study? (7) What is the differential diagnosis? ( (8) What additional diagnostic tests should be performed to restrict the differential diagnosis? (9) Additional information: Hepatitis A antibody is negative, as are hepatitis B core antibody and antigen and surface antigen. What is included in the differential diagnosis now? C 12 UCC 060759 Vinyl Chloride Toxicity Treatment and Management Acute Exposure After acute vinyl chloride exposure, the patient should be immedi ately removed from the source and given oxygen, if indicated. Any persistent effects should be treated symptomatically. Recovery from acute effects is usually rapid and complete with supportive therapy; there is no specific treatment or antidote for vinyl chloride exposure. There Is no specific treatment for patlente with acute exposure to vinyl chloride. Chronic Exposure In the past, symptoms associated with vinyl chloride disease tended to disappear within 1 or 2 years after the patient was removed from exposure. Hepatic angiosarcoma, on the other hand, grows rapidly and carries a poor prognosis; if untreated, most patients die within 6 to 12 months of diagnosis. Results of radiation therapy and chemotherapy have been disappointing. Patients who have had the tumor successfully resected have experienced long-term survival. Patients with chronic liver injury should avoid alcoholic beverages, tobacco use, and exposure to vinyl chloride, acetominophen, isoniazide, or other hepatotoxins. Follow-up may require treatment for complications such as ascites, diabetes, and bleeding varices. Unlike vinyl chloride disease, hepatic angio sarcoma has a poor prognosis. (10) What can you tell the patient described in the case study about hepatic angiosarcoma? How will you advise him? (11) What is the danger to other members of your patient's family and the community? What tests could you use to evaluate and monitor these persons? ucc 060760 13 J\TT!SDR Standards and Regulations The table below summarizes the standards and regulations for vinyl chloride, which are then discussed in greater detail. Table 1. Standards and regulations for vinyl chloride * Agoncy Focus Lavsi Comments ACGIH NiOSH Air-Workpiaca Air-Workplace 5 ppm 10 ppm 0 OSHA Air-Workplaca 1 Ppm 5 ppm EPA Air-Environment 10 ppm EPA Water 2 MO*- FDA Food 5-50 ppm Advisory; TWAf, continued human carcinogen Advisory; short-tern) Omit averaged over 15 minutes Advisory; zero exposure because o! carcinogenicity Regulation; PEL* over 8-hour workday Regulation; short-tom) limit not to exceed 15 minutes Regulation; emission limit Regulation; effective January 9,1989. tor aU water systems that regularly serve the same 25 persons at least 8 months/year Proposal; monomer content of polymers used in food packaging or processing ACGIH American Conference of Governmental Industrial Hygienists; EPA Environmental Protection Agency; FDA * Food and Drug Administration; NIOSH National Institute lor Occupational Safety and Health; OSHA * Occupational Safety and Health Administration *TWA (Time-Weighted Average) time-weighted average concentration tor a normal 8-hour workday and a 40-hour workweek to which nearly all workers may be repeatedy exposed. 9 PEL (Permissible Exposure Limit) highest level of vinyl chloride in air, averaged over an 8-hour workday, to which a worker may be exposed. Q The PEL set by OSHA Is 1 ppm averaged over an 8-hour workday. Workplace Air The Occupational Safety and Health Administration (OSHA) re quires that a worker's exposure to airborne vinyl chloride monomer not exceed i ppm averaged over any 8-hourperiod and thataworker not be exposed to greater than 5 ppm for any period of time exceed ing 15 minutes. Direct contact With the liquid is prohibited. 14 ucc 060761 Vinyl Chloride Toxicity The American Conference of Governmental Industrial Hygienists recommends an exposure limit of 5 ppm for an 8-hour day and a short-term exposure limit of 10 ppm. The National Institute for Occupational Safety and Health (NIOSH) has concluded that an expo sure level for vinyl chloride is inappropriate because of its carcino genicity. NIOSH has recommended that workers exposed to vinyl chloride wear an air-supplied respirator. NIOSH rcommand* a zero exposure limit for vinyl chlorlds. Environment Air The 1982 EPA emission standards for chemicals released to the atmosphere set a limit for vinyl chloride of 10 ppm, measured at the source. Water Pursuant to the Safe Drinking Water Act, EPA has issued a maxi mum contaminant level for vinyl chloride of 2 micrograms per liter (ug/L) or 2 parts per billion (ppb), effective January 9, 1989. This regulation applies to all community drinking water systems that regu larly serve the same 25 persons for at least 8 months of the year. Food The Food and Drug Administration (FDA) proposed in 1986 that the vinyl chloride monomer content of polymers used in food packaging or processing be limited to 5 to 50 ppm, depending on the nature of the polymer and its use. These levels would produce negligible amounts of vinyl chloride in the food. EPA hat Mt an amission standard of 10 ppm for vinyl chlorlds. Th* maximum contami nant level for vinyl chloride In drinking water I* 2 ppb. FDA limits the content of vinyl chloride monomer In PVC that Is used for food packaging. Cfurfktyjt (12) Where wouldyougethelp in orderto evaluate others living or working in the community nearthe former vinyl chloride facility and the workers who were employed at the plant? UCC 060762 15 Suggested Reading List General Bolt HM, Laib RJ, Kappus H, Buchter A. Pharmacokinetics of vinyl chloride in the rat. Toxicology 1977;7:l 7988. Buchter A, Filser JG, Peter H, Bolt HM. Pharmacokinetics of vinyl chloride in the Rhesus monkey. Toxicol Lett 1980;6:33-6. Dinman BD, Cook WA, Whitehouse WM, Magnuson HJ, Oitcheck T. Occupational acroosteolysis. An epi demiological study. Arch Environ Health 1971 ;22:61-73. Doll R. Effects of exposure to vinyl chloride. An assessment of the evidence. Scand J Work Environ Health 1988;14:61-78. Environmental Health Associates. An update of an epidemiological study of vinyl chloride workers 19421982. Oakland, CA: EHA Inc; 1986. Final report to the Chemical Manufacturers Association. Fox AJ , Collier PF. Mortality experience of workers exposed to vinyl chloride monomer in the manufacture of polyvinyl chloride in Great Britain. Br J Ind Med 1977;34:1-10. Perticoni GF, Abbritti G, Cantisani TA, Bondi L, Mauro L. Polyneuropathy in workers with long exposure to vinyl chloride. Electrophysio logical study. Electromyogr Clin Neurophysiol 1986;26:41-7. Preston BJ, Jones KL, Grainger RG. Clinical aspects of vinyl chloride disease: acro-osteolysis. Proc R Soc Med 1976;69:284-6. Hepatotoxlcity Berk PD, Martin JF, Young RS, et al. Vinyl chloride-associated liver disease. Ann Intern Med 1976;84:71731. Liss GM, Greenberg RA, Tamburro CH. Use of serum bile acids in the identification of vinyl chloride hepatotoxicity. Am J Med 1985;78:68-76. Popper H, Thomas LB. Alterations of liver and spleen among workers exposed to vinyl chloride. In; Selikoff IJ, Hammond EC, eds. Toxicity of vinyl chloride-polyvinyl chloride. Ann NY Acad Sci 1975; 246:172-94. Carcinogenicity Bolt HM. Metabolic activation of vinyl chloride, formation of nucleic acid adducts and relevance to carcino genesis. IARC Sci Publ 1986;70:261-8. Guengerich FP, Crawford WM Jr, Watanabe PG. Activation of vinyl chloride to covalently bound metabolites: roles of 2-chk>roethylene oxide and 2-chloroacetaldehyde. Biochemistry 1979;i 8(23) :5177-82. Hansteen IL, Hillestad L, Thiis-Evensen E, Heldaas SS. Effects of vinyl chloride in man: a cytogenetic follow up study. Mutat Res 1978;51:271-8. Heath CW Jr, Falk H, Creech JL Jr. Characteristics of cases of angiosarcomaof the liveramong vinyl chloride workers in the United States. Ann NY Acad Sd 1975;246:231-6. International Agency for Research on Cancer. Some monomers, plastics and synthetic elastomers and acrolein. Lyon: IARC,1979:377-438. (IARC monographs on the evaluation of the carcinogenic risk of chemicals to humans; vol 19). Technical Report No. 31. The mutagenicity and carcinogenicity of vinyl chloride: a historical review and assessment. Brussels, Belgium: European Chemical Industry Ecology andToxicology Centre; 1988. 16 ucc 060763 Vinyl Chloride Toxicity Teratologic Effects Edmonds LD, Anderson CE, Flynt JW Jr, James LM. Congenital central nervous system malformations and vinyl chloride monomer exposure: a community study. Teratology 1978;17:137-42. Theriault G. Iturra H, Gingras S. Evaluation of the association between birth defects and exposure to ambient vinyl chloride. Teratology 1983:27:359-70. Related Government Documents Agency for Toxic Substances and Disease Registry. Toxicological profile for vinyl chloride. Atlanta: US De partment of Health and Human Services, Public Health Service, 1989. NTIS report no. PB/90/103810/AS. Environmental Protection Agency. Health effects assessment for vinyl chloride. Cincinnati: US Environment al Protection Agency, Office of Environmental Criteria and Assessment, 1984. Report no. EPA 540/1-86036: NTIS report no. PB/86/134475. Answers to Pretest and Challenge Questions Pretest questions are found on page 1. Challenge questions begin on page 3. (1) Since the odorof vinyl chloride was detected by you r patient, you can conclude that the air concentration must have been high (300 to 5000 ppm) and that your patient received toxic doses on those occasions. You may want to determine if others smelled the vinyl chloride. In caseswhere plant records are available, it is desirable to obtain the frequency and extent of contamination Irom them. The drinking water in your patient's home should be tested since groundwater contamination, caused by a release from the plant, is a possibility. (2) in addition to exposure through possible contamination of the air and water at home, your patient may be exposed to vinyl chloride at work. As a car salesman, he may daily spend time inside new cars where the ambient air can contain significant amounts of vinyl chloride (1 to 10 ppm) released from plastic and up holstery, including the dashboard and seats. To the general population, this and other sources of consumer exposures to the monomer such as PVC food packaging and flooring are of little concern. (3) Those closest to the source of vinyl chloride, i.e., the formerworkers at the plant, are at highest risk. Assuming only air emissions from the plant, your patient's immediate family, the surrounding community, and especially those residents immediately downwind have probably been periocficaBy exposed. Since airborne vinyl chloride normally photodegrades within a few hours, ambient air exposure is likely to occur only a limited distance from the plant. If the groundwater has been contaminated, on the other hand, the number of persons affected could be far greater, and they could be located at some distance from the plant. (4) Your patient has lived near the vinyl chloride plant for 18 years. His chBdren may have been periodically exposed in their younger years, depending on their ages. Data from animat studies suggest that exposure at an early age may increase the risk of cancer later; however, there is no supportive human evidence. The patient's grandson has not been exposed to contaminated air because the plant shut down 2 years ago. Thera is no evidence that vinyl-chloride contaminated water would have any effect on the child, pre- or postnatalty. (5) Yes. It would be prudent to investigate all potentially involved organ systems, although there is no conclusive evidence that environmental exposures to vinyl chloride result in neurotoxicXy or cancers other than hepatic. (6) The patient's problem list includes fatigue, weight loss, and liver enlargement. 17 UCC 060764 TSDR (7) The differential diagnosis at this point might include the following: acute hepatitis (viral or alcohol-, chemical-, or drug-induced) chronic active hepatitis (viral types B, C, D) granulomatous or neoplastic infiltration Among causes of acute hepatitis, alcohol is less likely because the SGPT level is greater than the SGOT level. With normal alkaline phosphatase, primary biliary cirrhosis or bile duct obstruction are also not probable. (8) Viral hepatitis should be ruled out by serologic testing. Imaging studies such as CAT, MRI, or liver-spleen scan would be appropriate. An angiogram would be helpful if angiosarcoma is suspected. Direct indicators, such as urinary thiodiglycolic acid or vinyl chloride levels, would be helpful only if exposure to vinyl chloride were recent. Negative results in tests measuring these direct indicators, however, would not rule out drinking water contamination, for example. (9) The differential diagnosis now most likely includes cirrhosis and malignancy. Hepatic angiosarcoma is not normally prominent in the differential diagnosis of liver function abnormalities. However, the test results thus far and the fact that this is a nonoccupational exposure to vinyl chloride (nonmaiignant liver injury has not been reported in environmental exposures) make angiosarcoma of the liver a possibility. In the case of angiosarcoma of the liver, hepatic arteriography would reveal a characteristic appearance, with displacement of hepatic arteries, and a blush and "puddling" during the middle of the arterial phase. Percutaneous liver biopsy is contraindicated in cases of angiosarcoma because of the vascular nature of the tumor and the possibility of complicating thrombocytopenia or significant bleeding; laparoscopic biopsy would be more appropriate. (10) Hepatic angiosarcoma grows rapidly and carries a poor prognosis. If untreated, most patients die within 6 to 12 months after diagnosis. The only long-term survivors have had the tumor successfully resected. As a precaution you might suggest that the patient ventilate new cars before entering them for prolonged periods and drive with the window open to maintain ventilation. Until the drinking water at his home is tested, the family should use bottled water to avoid any possible exposure there. (11) Since the rest of the family and the nearby community may have had similar exposure to vinyl chloride, all should undergo periodic testing of transaminases, alkaline phosphatase, and serum bile acids to detect latent chemical injury. If these tests or an ICG clearance rate are positive for hepatic injury, biopsy may also be helpful. If the drinking water is not contaminated and there is no vinyl chloride waste disposal source to contaminate the water in the future, the exposure to the family and community has likely terminated. (12) Your local, county, or state health department should be contacted and notified of the possible case. Because hepatic angiosarcoma is an extremely rare disease, even one case would alert public health authorities to a potential risk to the community around this plant. Your report should initiate case-finding investigations among the formerworkers at the plant as well as in the community. Public health authorities may alsowantto evaluate the potential for groundwater contamination around the plant. Sources of Information More information on the adverse effects of vinyl chloride and the treatment and management of vinyl chlorideexposed persons can be obtained from ATSDR, your state and local health departments, and university medical centers. Case Studies in EnvironmentalMedicine: VinylChloride Toxicity is one of a series. For other publications in this series, please use the orderform on the back cover. Forclinical inquiries, contact ATSDR, Divisionof Health Education, Office of Director, at (404) 639-0730. 18 UCC 060765 Vinyl Chloride Toxicity Posttest Continuing education credit is available to health professionals who use this monograph and complete the posttest. The criterion for awarding CME credits and CEUs is a posttest score of 70% or better. The Centers for Disease Control (CDC) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to sponsorcontinuing medical education for physicians, and by the Council on the Continuing Education Unit (CCEU) to sponsor continuing education units for other health professionals. The Agency for Toxic Substances and Disease Registry, in joint sponsorship with CDC, is offering 1 credit hour of continuing medical education (CME) credit in category 1 of the Physician's Recognition Award of the American Medical Association and 0.1 hour of continuing education units (CEU) for other health professionals upon completion of this monograph. This program has been reviewed and is acceptable for 1 prescribed hour by the American Academy of Family Physicians (term of approval: through March 16,1991). For specific information, please consult the AAFP Office of Continuing Medical Education. The American College of Emergency Physicians (ACEP) has approved this program for 1 hourof ACEP Category 1 credit. The American Osteopathic Association (AOA) has approved this program for 1 credit hour of Category 2-B AOACME credit. To receive continuing education credit (CME or CEUs), complete the Posttest on page 20 in the manner shown in the sample question below. Circle all correct answers. Which of the following is known to precipitate migraine headaches? I fatigue alcohol C. grapefruit (gPsunlight e. sleep After you have finished the Posttest, please transfer your answers to the answer sheet on the Inside back cover and complete the evaluation on the lower half of that page. Fold, staple, and mail the back cover to Continuing Education Coordinator, Agency for Toxic Substances and Disease Registry, Division of Health Education, E33, 1600 Clifton Road, Atlanta, GA 30333. Your confidential test score will be returned with an indication of where the correct answers can be found in the text. Validation of earned CME credit and CEUs will also be forwarded to participants, and their names, if requested, will be placed on the mailing list to receive other issues in the Case Studies in Environmental Medicine series. 19 ucc 060766 =/^TSDR: POSTTEST: VINYL CHLORIDE Circle all correct answers and transfer your answers to page 21. 1. Which is true regarding the risk of exposure to vinyl chloride? a. there is no risk today b. workers in the PVC industry may be at increased risk c. chronic exposure may produce angiosarcoma of the liver d. those suffering from cardiovascular disorders have increased risk e. excessive alcohol consumption may increase the risk 2. Vinyl chloride is distributed in the body a. slowly because it is not well absotbed b. rapidly because it is very water-soluble c. rapidly because it is soluble in blood lipids and lipoproteins d. rapidly because of uptake by the erythrocytes e. slowly because it is excreted as a glucuronide 3. Chronic inhalation of vinyi chloride may result in a. malignant and nonmalignant liver injury, depending on exposure level b. a prehepatic sclerosis unique to toxic chemical exposure c. dermatitis d. hepatic fibrosis e. angiosarcoma of the liver 4. Neurologic effects due to vinyl chloride a. are not as great as once thought, which is why it is no longer used as an anesthetic b. may include peripheral neuropathy in chronic exposures c. can result in Parkinson's disease d. may result from vascular occlusions e. may include electroencephalographic changes 5. Angiosarcoma of the liver (ASL) a. is a common illness often associated with exposure to vinyl chloride b. will not result if the exposure to vinyl chloride ceases c. is a rare disease d. has occurred less frequently since workplace levels for vinyl chloride have been reduced e. has a latency period of 15 to 40 years 6. In the management and treatment of vinyl chloride-exposed patients a. the administration of a quick-acting antidote is essential in acute exposures b. recovery from a sublethal, short-term exposure is usually rapid and complete with supportive therapy c. patients should be encouraged to avoid alcohol d. viral hepatitis is often a compOcatlon e. the organ of primary concern Is the liver 7. Which is (are) important In the history and examination of patients exposed to vinyi chloride? a. a baseline chest X ray b. thorough evaluation of the liver and spleen c. alcohol consumption d. location of residence e. prior use of contraceptive steroids 8. Which of the following tests might be used to evaluate a patient exposed to vinyl chloride? a. serum bilirubin b. urinary coproporphyrin c. liver enzymes d. cardiac enzymes e. arterial pO, 20 UCC ,, 060^ 1 i Vinyl Chloride Toxicity f f ,< CASE STUDIES IN ENVIRONMENTAL MEDICINE: VINYL CHLORIDE II you wish CME credits or CEUs, please indicate your answers to the Posttest questions on page 20 by circling the letters below for the correct answers. Complete the evaluation questionnaire and fill in the information requested on the reverse side. Tear off this last page, fold, staple, and mail to Continuing Education Coordinator, Agency for Toxic Substances and Disease Registry, Division of Health Education, E33,1600 Clifton Road, Atlanta, GA 30333. 1. a b c d e 2. a b c d e 3. a b c d e 4. a b c d e 5. a b c d e 6. a b c d e 7. a b c d e 8. a b c d e Evaluation Questionnaire Please complete the following evaluation by circling your response. 1. Was the breadth of information in this issue sufficient lor your needs? Yes No Undecided 2. Was the amount of detail appropriate? Too technical Just right Not technical enough 3. As a result of reading this issue, will you now ask patients more questions regarding possible environmental exposures? Yes No Undecided Notapplicable 4. Would you recommend this issue to your colleagues? Yes No Undecided 5. Will you keep this issue as a reference? Yes No Undecided Comments: UCC 060768 21 To obtain credit please provide the requested information below. -------------------------------------------------------------------------------- --------------------------- - Name___________________________________________________ _ Address ________________ ____ _______________ _______ . , -___________________________________ Zip Check one: CME-AMA CME CME-ACEP CME-AOA CEU Contact Hours Specialty____________________________________ _______________________ To be placed on mailing list, check here. 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