Document mmq4o9DZ8Dq0VJmRwz8MO2yzJ

^W/C- frjJdSU- Pulmonary Manifestations of Vinyl and Polyvinyl Chloride (Interstitial Lung Disease)* Newer Aspects . M. Cordasco, AfJX, F.C.CJ\; S. L. Demeter, M.D.; J. Kerkay, Ph.D.; H. S. Van Ordstrand, M.D., F.C.CF.; E. V. Lucas, M.D.; T. Chen, Ph.D.; and]. A. GoUsh, MD., F.C.C.P. Vol. 78, p. 828*834 December 1980 Issue Reprinted from CHEST BFG07328 Pulmonary Manifestations of Vinyl and Polyvinyl Chloride (Interstitial Lung Disease)* Newer Aspects E. M, Cordasco, M.D., F.C.C.P.; S. L. Demeter, M.D.; ], Kerkay, Ph.D.; H. S. Van Ordstrand, M.D., F.C.C.P., E. V. Lucas, M.D.; T. Chen, Ph.D.; and]. A. Golish, M.D., F.C.C.P. Newer varieties of occupational lung diseases primarily due to the vast increase in industrial technology have been reported recently. Preeminent among such newer agents are vinyl chloride (VC) and polyvinyl chloride. Very few cases have been reported, in Europe only, with descrip tive histopathologic changes. To oar knowledge, no path ologic studies of VC exposure have been described in the American literature. The biopsy abnormalities in our patients disclosed desquamation of alveolar macrophages into the alveolar lamina and minor interstitial and alveolar inflammatory changes. Pulmonary function ab normalities included restrictive insufficiency. Preventive therapy consists of the avoidance of further exposures, frequent industrial hygiene monitoring, and total avoid ance of tobacco smoke, as well as associated atmospheric pollutants. Thus far, none of these patients has exhibi ted evidence of pulmonary neoplasm. All three patients survived their occupational Injuries, and two are stfll disabled to varying degrees. Urine and blood levels of phthalic add derivatives were elevated in two patients, the exact significance of which is not fully known. It probably represents a toxicologic response, but must be further pursued before conclusions can be reached. 1VT ewer varieties of occupational lung diseases have ^ " been reported recently, primarily due to pro found advances in industrial technology. Preeminent among such newer agents are vinyl chloride (VC) For editorial comment see page 826 and polyvinyl chloride (PVC), substances used ex tensively in the plastics industry. More than 18 bil lion lbs were produced in 1972, with approximately 25 percent produced in the United States. Between 36,000 and 50,000 workers were exposed at that time to VC or PVC fumes, either during the polymeriza tion process or during the processing of finished products.1 The number of people exposed, owing either to alteration of the finished product or de- 'From the Cleveland Clinic Foundation and Cleveland State University, Cleveland; and Northeastern Universities School of Medicine, Ravenna, Ohio. Manuscript received August 29; revision accepted January 29. Rejjrint requests: Dr. Cordasco, 9500 EucUa Avenue, Cleve land 44106 struotion of these products, or simply to living near a plant where any of these diverse processes may take place, is unknown. However, evidence has been pre sented that such exposures may be harmful. Accord ing to a recent Environmental Protection Agency report, approximately 90 million kg of PVC are discharged annually into the atmosphere.2 The emergence in 1974 of VC as a new occupa tional carcinogen, producing angiosarcoma of the liver, focused attendcm on other toxicologic manifes tations of this group of chlorinated hydrocarbons. Pulmonary effects were first described in 1970, but few cases have been reported characterizing the histopathologic changes of the human respiratory tract, all published from abroad. Three patients with extensive exposure to the fumes of either VC monomer or PVC are herein reported. Lung biopsy results and the implications of their exposures are discussed. In addition, ultramicroscopic findings are included, and new bio chemical analyses are reported in two patients. A summary on this subject of PVC-induced disease was presented by the authors at a symposium in the Soviet Union in October, 1978.* Materials and Methods Our experience involves the diagnosis and management of three patients with a pathologic diagnosis of interstitial fibro sis and work-related exposure to either VC or PVC gas or solids. All three patients had a lung biopsy, one transbronchial, and one by open method. Pulmonary function studies were done by the Systems Research Laboratory method and included total vital capac ity, timed vital capacity, flow rate, and diffusion capacity with carbon monoxide. Arterial blood gas determinations were performed by die Instrumentation Laboratory method, and distribution studies were measured with the nitrogen washout method. Routine screening tests included complete blood counts (CBC), urinalysis, serology, SMA-12 chemistry profile, ECGs, and sputum studies for routine bacteriology. Smears and cultures of sputum for fungi and Mycobacterium were also performed. Each patient also had a sputum cytologic examination. Immunologic testing was performed on each patient and is detailed under the case discussion. 828 CORDASCO ET AL CHEST, 78: 6, DECEMBER, 1980 BFG07329 Case 1 A. 55-year-old woman had an 19-month history of cough and fatigue and a six-month history of progressive dyspnea and digital cyanosis. At the present time die cough is dry, occurring in paroxysms; it may be initiated by breathing deeply or changing positions. Medical history, family history, travel history, and review of systems were noncontributory. She had never smoked or had any pulmonary symptoms until the onset of her present illness. For the last 20 years the patient has been employed as a Fzgobe 1A. X-ray of chest. Diffuse nodular pneumonitis. Ficure IB and 1C. Diffuse fibrosing pneumonitis with inter stitial thickening and desquamation of cells into alveolar himen. meat wrapper. The process involves cutting and sealing the plastic wrap by melting it on a hot wire or hot plate. She also worked with adhesive label stamping during the past year. She has never experienced cough or shortness of breath in relation to her work exposure. However, she does state that her fatigue is more profound as the week goes on and that each Sunday night is her best time. The fatigue has lessened now that she limits her work to two-day periods. Physical examination results were normal except for the lungs and hands. There were fine inspiratory crackles heard diffusely over the lung fields, but more prominently at the bases. There were no wheezes. All fingers showed dubbing; this appar ently had occurred over the last six months. Her toes were normal. Laboratory values, which were normal, included CBC, liver and renal function tests, urinalysis, and EGG. A hyper sensitivity screen for various fungi was negative. The sedi mentation rate, latex fixation, rapid plasma reagin (RPR), antinuclear antibody (ANA), and Clq were all normal. Circulating immune complexes by Clq-binding assay were negative. The lymphocyte transformation test against PVC was also negative. The chest x-ray film revealed diffuse reticulonodular changes. Doppler ultrasound examination of the fingers demonstrated decreased blood flow, more pro nounced after cold exposure. Pulmonary function study dis closed a restrictive abnormality (die vital capacity was 61 percent of predicted normal), with a diffusing capacity (DLco) of 11.2. Other new tests included a blood level for the measurement of phthalic acid derivatives, namely phthalic anhydride, a decomposition product of PVC, which measured 82.8 ng/ml, which is considerably elevated. The urine test for thermoplastic products revealed a remarkable elevation of two components--the phthalic anhydride deriva tive diethylhexyl phthalate known as DEHP, and another component that has been unidentified to date and is probably a fatty acid ester. These tests were performed at the Cleve land State University Biochemical Laboratories. It is the opinion of the biochemists that these levels are significant and have been demonstrated in animal studies using PVC tubing when the E factors are at a range associated with the release of thermoplastic resins and derivatives. This aspect of the study is still being assessed, and a future report is planned for publication. It was thought that interstitial fibrosis accounted for the patient's signs, symptoms, and laboratory abnormalities. It was further thought that she also showed signs of PVC exposure toxicity with digital angiitis. We postulated that the interstitial fibrosis may have been induced by her PVC exposure. Accordingly, she underwent an open long biopsy of the right lower lobe for pathologic confirmation. An x-ray film of the chest disclosed a diffuse nodular pneumonitis without localized disease (Fig 1A). There were no pleural or hilar abnormalities. Light microscopy (Fig IB and 1C) demon strated diffui fibrosing pneumonitis with prominent terminal bronchiolar cell hyperplasia of the alveolar lining or desqua mation. Immunofluorescence was negative for complement and immunoglobulins. Large numbers of alveolar macro phages containing phagocytized material of undetermined composition was seen on electron microscopy (Fig 2). All cultures of lung tissue were negative. The special blood and urine studies for thermoplastic resins were positive and will be further pursued. The patient was discharged receiving 40 mg of prednisone per day. Comment: This patient showed nonspecific signs and symptoms of fibrosing interstitial pneumonitis, which was CHEST, 78: 6, DECEMBER, 1980 PULMONARY MANIFESTATIONS OF VINYL AND POLYVINYL CHLORIDE 829 BFG07330 r----'-------- f rh. Ficuhe 2. Alveolar macrophages with phagocytized ma terial (electron micrograph). confirmed by biopsy specimen. There was apparently no evidence of a hypersensitivity reaction either by history (type II), laboratory (type IV), or immunopathology (types II or III), according to tire criteria proposed by McComb* as a modification of the Gell and Coombs classifi cation. Digital angiitis, as demonstrated here, can be a manifestation of PVC toxicity. Case 2 A 41-year-old man complained of "not feeling well." For the past 3X years he had experienced vague feelings of not being in good health, with weakness, fatigue, diffuse arthalgias, and myalgias. In die last eight months he had noticed an accentuation of his symptoms as well as dyspnea on exertion, wheezing, and a productive morning cough. A diagnosis of asthmatic bronchitis was made at that time, and he was given multiple drugs without improvement. Three months before referral, he was hospitalized at another institution for further evaluation. A bronchoscopy was nega tive, and transbronchial lung biopsy of the right lower lobe was reported to show pigmented macrophages in the air spaces. The chest x-ray film showed increased interstitial markings. Sputum examination showed moderate WBCs and alveolar macrophages. Laboratory test results, which were normal, included latex fixation, ANA, VDRL, ECG, and sputum cytology. Serum Immunoelectrophoresis revealed de creased IgM, slightly decreased IgA, and normal IgC. Pul monary function studies showed a decreased Pa02 with small airway disease. An exercise tolerance test was performed and indicated that the patient was capable of moderate exercise. He was given bronchodilators and antibiotics, with no re 830 CORDASCO ET Al sponse, and later, corticosteroids (for suspected connective tissue disease) with a favorable response. He returned to work after two weeks and again noticed myalgias and arthralgias, easy fatigability, exhaustion toward the end of the day, and stiffness in his joints. He was referred to this institution for further evaluation. For the past 14 years he had been employed in the dental mold industry and had extensive daily use of VC spray paint. Review of systems, family history, medical history, and expo sure history were otherwise negative. He had smoked one half pack of cigarettes per day for the last five years. The initial physical examination results were normal. The lungs were clear. A rheumatology consultation revealed no evi dence of connective tissue disease. Laboratory and roentgenographic examinations were positive for osteoarthritis. Normal or negative laboratory tests included an ECG, serum T,, T4, anti-thyroid binding globulin, VDRL, sedimentation rate, latex fixation, LE cell prep, ANA, urinalysis, CBC, SMA-28, and serum protein electrophoresis. The chest x-ray film showed diffuse, smalt interstitial, and nodular densities scattered throughout both lungs. The patient returned to work. His symptoms were stable over the next two months; however, two days before his admission, he complained .of a "flu-like" syndrome, with an increase in his generalized aching, a slight, dry cough, an increase in shortness of breath, and chest tightness. On examination he was afebrile, with few bibasilar crepitant rales and a palpable lymph node in the right supraclavicular fossa. An immunoglobulin electrophoresis now showed in creased IgA (330; normal, 156 -. 92), low normal IgM (51; normal, 145 105), and decreased IgG (950, normal, 1,380 255). The remainder of laboratory and physical examina- CHEST, 78: 6, DECEMBER, 1980 BFG07331 i :; ;f tion results were unchanged. The chest x-ray film was un changed and was interpreted by the 1LO/UC classification as being 1/1. On biopsy, the lymph node showed histiocytosis consistent with chronic inflammation. He underwent a trephine lung biopsy, which was reported to show large numbers of alveolar macrophages in die alveolar air spaces, thickening of the peribronchiolar connective tissue, and al veolar septa with accumulation of mononuclear cells and anthracotic pigmentation, hypertrophic bronchiolar epithe lium, and macrophages containing large amounts of hemo siderin and a few anthracotic pigments (Fig3). The patient was discharged receiving corticosteroids, with gradual clearing of his symptoms over the next 2X years. Follow-up laboratory examination results have remained un changed. The chest x-ray film has remained abnormal. Comment; The biopsy specimen showed changes con sistent with interstitial fibrosis; no immunologic testing was performed on the tissue. This patient differs from patient 1 in that his exposure was to the VC monomer as opposed to PVC fumes. Cask 3 This 55-year-old man was exposed to PVC dust during a reactor cleaning operation. He was a nonsmoker. His initial exposure occurred over a five- to six-week period, resulting in the development of continuous and progressive dyspnea of approximately ten days' duration. He had severe dyspnea in the 24-hour period before admission. Air samples of PVC in the immediate operational area varied between 200 and 315 parts per million. Examination of the chest showed bibasilar coarse, inspiratory, crepitant rales. Because he initially failed to respond to oral aminophyl- line therapy prescribed by his local physician, steroids and high-flow oxygen with a Venturi-type mask were added, with considerable subsequent improvement over the next 48 to 72 hours. There was a gradual reduction of die steroid dose over the next two-week period as the patient showed progressive improvement Concomitantly, there was complete resolution of the roentgenographic lesions. The pulmonary function tests in this person disclosed a moderate reduction of vital capacity and in the mid-expiratory flow rates and moderate impair ment of diffusion capacity to 12.8. The arterial PaO, mea sured 60 mm Hg at room air. The remainder of the routine laboratory studies, which included an SMA-L2 chemistry profile, urinalysis, serology, and CBC, were normal, except for minimal leukocytosis of 12,200 cells. Figure 4b shows his chest x-ray film at the time of the six-week exposure. The histopathologic changes were compatible with a desquama tive interstitial pneumonitis. The section of his lung biopsy disclosing these findings is shown in Figure 4a. Discussion Figure 4A. Chest x-ray film abnormality; interstitial infil trates. Figure 4B. Desquamation of cells into alveolaT lumen. Vinyl chloride (CHs = CHC1) is a monomer used as a chemical intermediate in the polymerization of PVC resin in the production of copolymers such as Saran, and as a solvent.8 VC monomer under normal temperature and pressure is a gas (BP 13.5 C). It readily polymerizes under pressure at a temperature of 40 to 70 C to form PVC, a white, solid material. Although the polymerization process was discovered in the 1800s, PVC production did not begin in the United States until 1928. The list of materials made from PVC is extensive and includes foils, films, tapes, tubing, fiber, cables, artificial leather, foam rubber, paint, varnish, toys, and automobile up holstery coverings. The acute, toxic effects of VC gas (anesthesia and narcotic-effect) were quickly discovered and were thought to represent the only toxic effect of exposure until 1949, when Tribukh et al6 in Russia reported a hepatitis-like effect following long-term exposure. Other toxic manifestations were reported during the 1960s (Table 1), and in 1974, the association be tween VC exposure and angiosarcoma of the liver was made. Further toxic manifestations were discov ered during epidemiologic studies that were per formed both on production workers and on popula tions living near the plants. The clinical spectrum of PVC-induced toxic organ damage is broad (Table 1). The most widely reported manifestation is a scleroderma-like syndrome, and the most widely dis cussed is the angiosarcoma of the liver. Table 2 lists CHEST, 78: 6, DECEMBER, 1980 PULMONARY MANIFESTATIONS OF VINYL AND POLYVINYL CHLORIDE 831 & BFG07332 Table 1--'Toxic Effect* of VC and PVC Exposure by Organ System. Organ Toxic Effect(s) Reference^) Liver Hepatitis (elevated enzymes) Hepatomegaly or abnormal liver scan Hepatic fibrosis Angiosarcoma 30,31 31,32 30 30,31 Skin Dermatitis (resembles scleroderma) 2,29 Vascular Digital angiitis (resembles Raynaud's) 3,29,30 Hematologic Thrombocytopenia 24,29 Skeletal Acroosteolysis 3,29 Pulmonary Acute airflow obstruction Chronic airflow obstruction Interstitial fibrosis 4,22 6,7 21,22,32 other manifestations of PVC toxicity. Other than the acute narcosis, the diseases on this list were discov ered by epidemiologic studies and were thought to represent statistically significant association. The teratogenetic effect applies to communities sur rounding PVC production plants. The effects of VC and PVC exposure on the pul monary system include both acute and chronic air flow obstruction. "Meat wrapper's asthma" is a syn drome of acute bronchospasm due to the inhalation of PVC fumes from melted plastic wrap. It closely resembles an acute hypersensitivity response that can be seen with other industrial exposures, but no documented immunologic complexes have been re ported to date,7 with one exception: a report from abroad.8 Decreased flow rates are also seen with chronic exposure. One study found a decreased FEVi/FVC ratio in 30 percent and SO percent of nonsmokers with one to 20 years and more than 20 years of exposure, respectively. Another study found decreased flow rates in 50 percent of PVC production workers who were older than 30 years.10 Others have disputed such claims.11 We have re cently encountered three patients with PVC-induced asthma. This is the subject of a separate report.12 Table 2--Nonorgan System Toxic Manifestations of VC and PVC Exposure Effect Acute narcosis Increased mortality Increased cancer rates Chromosomal abnormalities Increased teratogenicity and fetal mortality Reference^) 33 16,34 10,13,16,16,35 5,36,38,39 35,37,40 832 C0RDASC0 ET AL The risk of pulmonary neoplasms may also be higher in VC and PVC production workers. Animal data are highly suggestive,1*15 but the standardized mortality ratios (SMRs) vary from 112,10 156,17 160,18 to 168,19 and other studies could find no increase in the expected amount of cancer.2*22 Another study supports a carcinogenic effect be cause of differences in expected cell types (with no increase in the total number of lung cancers).24 In addition, the effect of concomitant cigarette smoking is unknown but probably additive. Other industrial exposures (eg, asbestos, chromium, and chloromethyl ether) indicate a probable synergism in car cinogenic effects. The cell types of lung neoplasms reported by Waxweiler are shown in Table 3. Interstitial fibrosing pneumonitis due to PVC or VC exposure has been reported only rarely,2*25 primarily from the foreign literature, although nodu lar infiltrates on chest x-ray film have been described in 3/37 workers in one report.27 Of 985 workers in another study, 13.3 percent showed a similar abnor mality (1/0 or 1/1, ILO/UC classification).10 Inter stitial changes have also been delineated in experi mental animals.28 We report three further cases of histologically proved interstitial fibrosing pneumonitis in patients exposed to either VC or PVC fumes. Signs, symp toms, and laboratory abnormalities do not differ significantly in patients with interstitial disease asso ciated with VC or PVC exposure from those with idiopathic interstitial fibrosis. Usual symptoms in clude the insidious onset of dyspnea, exertional weakness, and dry cough. Physical examination re veals fine bibasilar inspiratory crackles. Other signs of PVC toxicity may be seen as well. The chest x-ray Table 3--Lung Cancer Cases Histologically Confirmed Among Cohort Workers Exposed to Vinyl Chloride!Polyvinyl ChlorideTM Case No. Histologic Diagnosis Age at Death, Exposure, Latency, yr yr yr 1 Large cell undifferentiated 39 14 15 2 Large cell undifferentiated 40 13 18 3 Large cell undifferentiated 52 22 22 4 Large cell undifferentiated 61 16 17 5 Large cell undifferentiated 61 8 17 6 Adenocarcinoma 45 19 19 7 Adenocarcinoma 57 12 12 8 Adenocarcinoma 72 15 22 9 Mesothelioma (?; possible, our patient) 12 28 CHEST, 78: 6, DECEMBER, 1980 90832802 BFG07333 p rs film shows diffuse,reticulonodular infiltrates; pulmo nary function testing demonstrates a restrictive pat tern and depression in the DLco with variable levels of PaOa. Lung biopsy specimen discloses interstitial infiltration with mononuclear cells, fibrosis, alveolar hyperplasia, and desquamation into the alveolar lumina. Diagnosis is best confirmed by lung biopsy. At present it is highly presumptive, but strongly indicated, that there is an association between the exposures and the development of interstitial fibros ing pneumonitis. No cause-effect relationship can categorically be proved with certainty in such a small series. However, the patient with a history of exposure in the polymerization process coupled with the clinical studies of other authors (Lilis, Meloni, and Szende) almost certainly substantiates the diag nosis, at least in the one patient. The mechanism of the response remains specula tive, although a dysfunction in the immune system is probably implicated. Of 320 workers in a VC poly merization plant, 28 were found to have Raynaud's phenomenon, and 19 of the 28 were found to have circulating immune complexes.8 Circulating cryoimmunoglobulins are found in 41 percent erf patients with usual interstitial fibrosis and play an etiologic role.29 In addition, markers of abnormalities of the immune system (ANA, latex fixation, sedimentation rate) are found in approximately 25 to 30 percent of patients with fibrosing alveolitis.20 It is tempting but purely hypothetical to speculate on an immuno logic basis for this response, despite die total ab sence of these markers in our patients. The other mechanism is toxicologic, namely, dose-effect rela tionship to exposure. In his review of idiopathic pulmonary fibrosis. Crystal81 points to several "dues" in attempting to answer the question "What triggers the disease?" Some "triggers" (or etiologic factors) found in pa tients with interstitial fibrosis may indude: (1) in fection (25 to 40 percent of patients antedate their illness to a viral chest syndrome); (2) hereditary factors (familial dusterings and relative increase in HLA-12 and HLA-29); and (3) cell-mediated im mune reactions (directed against lung collagen). Perhaps toxic exposures eventually will find their place in this list as more associations of die type we have just presented are brought to light. The identification of diethylhexyl phthalate (DEHP) in the serum and urine of excessive amount (190 times that of the control) in one pa tient is interesting and presumably significant. Re cently, similar elevations of the substance in both serum and urine were identified in the second pa tient The substance is a decomposition product of PVC chemically similar to dicyclohexyl adipate. It accompanies dicydohexyl adipate, a major emission during hot-wire cutting of meat wrap plastic, as another plasticizer present in PVC. It may also occur as a decomposition product during the adhesive stamp-labeling process. The major ingredient of the latter process is dicydohexyl phthalate. Four major thermal decomposition products of dicyclohexyl phthalate are cydohexanol, dicydo hexyl ether, phthalic anhydride, and cyclohexyl ben zoate. The presence of these compounds, along with DEHP, was readily demonstrated in the serum and urine of two patients. In addition, urine samples also contained significant amounts of MEHP (monoethylhexyl phthalate), phthalic add, benzoic acid, and O and P-hydroxy benzoic add. These urine components are probably metabolites of DEHP and other plasticizers present in PVC. Complete evalua tion erf the metabolism erf decomposition products of PVC in man is presently being pursued at Cleveland State University. Treatment is primarily prophylactic, with imme diate removal of the affected patients from the of fending fumes being of paramount importance. Corticosteroids may be helpful in the treatment of the early stages of this disease. Other immunosup pressive agents have not been used, to our knowl edge. The efficacy of steroids was verified in one of our patients and is highly probable in our second patient who had long-term exposure to PVC fumes. The use of other immunosuppressive agents has not been reported to our knowledge. Prophylactically, frequent industrial hygiene monitoring is of utmost importance for the early detection of abnormal at mospheric levels in the occupational environment. Close medical surveillance of such persons exposed may prevent the occurrence of severe adverse health effects. Conclusions The awareness erf newer hazards of chemical sub stances increasingly present in our environment is of paramount importance to every employee, as well as to the entire community, because of the obvious occupational and public health implications. Exam ples of such newer agents have been reported. Newer biochemical studies of both the serum and urine, notably decomposition products of thermo plastic resins of the phthalic acid group, were ab normal in two.patients. The total clinical significance of these factors is yet unknown and will be further pursued. f^This is one of the first reports in this country to delineate the histopathologic changes of the respira tory tract that constitute such excessive exposures of the VC/PVC groupT^iherapeutic implications in clude the necessity ofearlier medical surveillance as CHEST, 78: 6, DECEMBER, 1980 PULMONARY MANIFESTATIONS OF VINYL AND POLYVINYL CHLORIDE 833 00328021 BFG07334 -*T-' * - U. well as the institution of diagnostic and prophylactic industrial hygiene procedures on a more frequent basis. This is of paramount importance, since VC and PVC are toxic agents. Therefore, it is of utmost significance to institute such close medical surveil lance to prevent serious adverse health effects. References 1 Berk PD (mod). Vinyl chloride-associated liver disease. Ann Intern Med 1978; 84;717-31 2 Twit C. Occupational medicine principles and practices application. Chicago: Year Book Medical Publishers; 1975:789 3 Cordasco EM, Demeter S. Pulmonic manifestations of polyvinyl chloride exposures. Presented at Symposium, Republic Hospital, Dusambe, Tajikistan, USSR, October 1978 4 McCoombs RP. Disease due to immunologic reactions in the hmgs. N Engl J Med 1972; 286:1186-94; 1245-52 5 Heath C, Falk H, Creech J. Characteristics of cases of angiosarcoma of the liver among vinyl chloride workers in fire United States. Ann NY Acad Sci 1975; 246:231-36 6 Kramer CG, Mutchkr JE. The correlation of clinical and environmental measurements for workers exposed to vinyl chloride. Am Ind Hyg Assoc J 1972; 33:19-30 7 Sokol WN, Aelony Y, Beall GN. Meat-wrapper's asthma: a new syndrome? JAMA 1974; 222:639-41 8 Ward AM, Udnoon S, Watkins J, Walker AE, Darke CS. Immunological mechanisms in the pathogenesis of vinyl chloride disease. Br Med J 1976; 1:936-38 9 Miller A, Teirstein A, Chuang M, Selikoff S, Warshaw R. Changes in pulmonary function in workers exposed to vinyl chloride and polyvinyl chloride. Ann NY Acad Sci 1975;246:42-52 10 Selikoff S, discussant in Barnes AW. Vinyl chloride and the production of PVC. Proc R Soo Med 1976; 69:277- 81 11 Gamble J, Liu S, McMiohael AJ, Waxweiler HJ. Effect of occupational and nonoccupational factors on die respira tory system of vinyl chloride and other workers. J Occup Med 1976; 18:659-70 12 Cordasco EM, Demeter S, Lira R, Wagner W, Occupa tional asthma updated. J Occup Health Safety 1980; 49:42-45 13 Lee CC, Bhandari JC, Winston JM, et aL Carcinogenicity of vinyl chloride and vinylidene chloride. J Toxicol En viron Health 1978; 4:15-30 14 Viola PL, Bigotti A, Capato A. Oncogenic response of ret skin, lungs, and bones to vinyl chloride. Cancer Res 1971; 31:516-22 15 Maltoni C, Lefemine G. Carcinogenicity bioassays of vinyl chloride: current results. Ann NY Acad Sci 1975; 248:195-218 16 Tabershaw JR, Gaffey WB. Mortality studies of workers in the manufacture of vinyl chloride Occup Med 1974; 16:509-18 its polymers. J 17 Waxweiler RJ, Stringer W, Wagoner JE, et aL Neoplastic risk among workers exposed to vinyl chloride. Ann NY Acad Sci 1976; 271:40-48 18 Monson RR, Peters JM, Johnson MN. Proportional mortal ity among vinyl chloride workers. Lancet 1974; 2:39798 19 Byren D, Engholm G, England A, Westerholm P. Mortal ity and cancer morbidity in a group of Swedish VCM and 834 CORDASCO ET AL PCV production workers. Environ Health Perspect 1976; 17:167-70 20 Dude DW, Carter JT, Coombes EJ. Mortality study of workers in a polyvinyl chloride production plant. Lancet 1975;2:1197-99 21 Falk H, Waxweiler R. Epidemiological studies of vinyl chloride health effects in the United States. Proc R Soc Med 1976; 69:303-06 22, Saric M, Kulcar Z, Zorica M, Gelic L Malignant tumors of the liver and lungs in an area with a PVC Industry. Environ Health Perspect 1976; 17:189-92 23 Mason TJ. 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Antibodies in some chronic fibrosing lung disease: L Non-organ-specific anti bodies. Clin Allergy 1971; 1:83-95 31 Crystal RG. Biochemical concepts and overall perspective of idiopathic pulmonary fibrosis, in Crystal RG. Idiopathic pulmonary fibrosis. Atm Intern Med 1970; 85:783-85 32 Veltman G, Lange C-E, Juhe S, Stein G, Bachner V. Clinical manifestations and course of vinyl chloride dis ease. Ann NY Acad Sci 1975; 246:6-17 33 Lilis R, Anderson H, Nicholson WJ, et aL Prevalence of disease among vinyl chloride and polyvinyl chloride workers. Ann NY Acad Sd 1975; 246:22-41 34 Creech JN. Industrial screening, in Berk PD (modera tor). Vinyl chloride-associated liver disease. Ann Intern Med 1976; 84:720-22 35 Marsteller HJ, Lelbach WE, Mueller, R, Gedigk P. Un usual splenomegalic liver disease as evidenced by peritonoscopy and guided liver biopsy among polyvinyl chlor ide production workers. Ann NY Acad Sci 1975; 246:95-134 36 Wagoner JE, Infante PF, Saracci R. Vinyl chloride and mortality? Lancet 1976; 1:194-95 37 Infante PF, Wagoner J, Waxweiler R, Carcinogenic, mutagenic and teratogenic risks associated with vinyl chloride. Mutat Res 1976; 41:131-42 38 Purchase IFH, Richardson CR, Anderson D. Chromo somal and dominant lethal effects of vinyl chloride. Lancet 1975; 2:410-11 39 Funes-Cravioto F, Lambert B, Lindsten J, et aL Chromo some aberrations in workers exposed to vinyl chloride. Lancet 1975; 1:459 40 Infante PF, Wagoner JK, McMichael AJ, Waxweiler RJ, Falk H. Genetic risks of vinyl chloride. Lancet 1976; 1:734-35 CHEST, 78: 6, DECEMBER, 1980 T t 20826008 BFG07335