Document G6e00YLe0LmzbgQOanvxKZZk7

4 fc (/U, J.- UOEH, 5 Suppi.: 37 --48(1983) The Identification of Hepatic Injury and Hepatic Angiosarcoma Among Vinyl Chloride Workers - The Epidemiological Approach C.H, Tamburro, M.D. and J.L. Creech, Jr., M.D. Departments of Community Health, Medicine and Surgery, Division of Occupa tional Health and Liver Research Center, School of Medicine, University of Louisville, Health Sciences Center, Louisville, Kentucky 40292, U.S.A. Introduction Hepatitis-like liver changes in vinyl chloride polymerization workers were reported in 1949 by Tribukh et al. [1]. In 1967, Creech et al_. reported the occurrence of occupational acro-osteolysis in vinyl chloride workers [2] and eight years later Identified the first case of human liver angiosarcoma [3]. Although these occupationally-related diseases were observed by astute Indus trial physicians, the establishment of a causal-relationship between liver disease and occupational exposure to vinyl chloride took 25 years. Industrialized societies throughout the world have become concerned over the potential health hazards of synthetic agents In the occupational environ ment. Screening programs have been instituted In work environments suspected or proven to have toxic or carcinogenic agents present; the primary objective ''v Is to reduce disability, morbidity and mortality In the workplace, especially as related to serious low-grade health hazards. Nearly all screening programs are started retrospectively and few have been instituted with any prior know ledge as to their effectiveness or capability of early detection and future prevention. These retrospective approaches Invariably deal with occupa tionally-related disease after its clinical manifestation has become overt and the causative connection has been made. Establishing a connection between toxic injury and exposure, and especially cancer development in the work environment, has been difficult due to the slow development of Injury, the long duration for malignancy to appear, the lack of uniform methods for moni toring the Incidence and prevalence of medical disease, the limitations of devices for exposure monitoring, and the non-availability of a control popula tion similarly monitored. The discovery of hepatic angiosarcoma In vinyl chloride workers In the United States by Creech provided the Impetus for the development of an ozeso'Ian ' 38 Industrial prospective occupational health surveillance system [4], Although this system was initially developed to Identify occupationally-related cancers [5], It Is equally capable of Identifying other potential occupationally-re lated medical disorders. This system Is not intended as a substitute for determining the safety of chemicals by chemical structural analysis, bacterial screening [6], tissue [7], or animal exposure studies [8] prior to their in troduction into the Industrial environment, but rather is a complementary, primarily preventive system directed at humans. Its structural development builds on already existing occupational, environmental, and medical data available or accessible through Industrial and medical records. The develop ment, implementation and evaluation of an operating prototype prospective occupational health surveillance system, begun In 1974, will be discussed herein. Occupational Health Surveillance System The occupational health surveillance system (OHS) can be applied retro spectively but Is best Instituted prospectively and consists of three programs or levels of complexity. Level I: Epidemiological Surveillance Program (ESP) Level II: Medical Surveillance Program (MSP) Level III: Medical Disease Detection and Treatment Program (MDDTP) The various levels of the OHS system are comparable to three major industrial environments [9]. Utilization of all levels of the OHS system constitutes a comprehensive medical surveillance program. However, all the various levels may not be needed In every Industry nor at every plant of the same Industry. It Is necessary, therefore, to determine into which category an Industry fits In order to assign the appropriate level(s) of surveillance. Classification of Industrial Environments All industrial or occupational-environments, depending on their toxic or carcinogenic potential, fall into one of three major categories. Category A includes all Industries or occupations in which the Industrial materials used have not yet been studied for toxic or carcinogenic capability. Category 8 includes all those Industries or occupations utilizing gh cers -refor rial in ary, ment data loptlve ssed trorams rial -s a /els :ry. its : or rial ty. zing 39 materials suspected of being potentially toxic or carcinogenic from labora tory, animal or human studies. Category C includes all Industries or occupations utilizing agents known to be toxic or carcinogenic, especially to humans. The OHS system's three major programs are appropriate to the different industrial categories listed. The OHS system's basic program, the ESP, is designed for Industries or occupations in Category A. The next program level, the MSP, is appropriate for Category 8 industries. The MDOTP Is the most com plex and is designed for Category C industries or occupations. Epidemiological Surveillance Program - Level I The prospective epidemiological approach requires accurate and complete data. The data collected must identify and characterize all the agents that workers are exposed to, and also identify the medical illnesses and disorders within the worker cohort. In The ESP consists of four components. 1. A standard job classification code. 2. An employee work history record. 3. A rank ordered exposure rating system. 4. A medical illness and disease data base. The standard job classification code identifies Individual jobs based on their activities or function. An example of this is shown In Table 1. Employee work history records should begin with first time employed, should be continuous, include all transfers from job to job, and should be carried from company to company. No employee activity or responsibility should be without a job classification code. The code should Include a spe cific listing of all agents or potentially harmful activities involved with that job. URL 05322 40 Table 1 GENERAL LISTING - WORK HISTORY COPING SYSTEM CORK ASSIGNMENT HOVE BASES JOB COOES POLYMERIZATION OPERATORS ANY BUILDING EXCEPT AS LISTED DLLOV A. CHARGING OPERATOR - GEN. B. CHARGING OPERATOR - PVC C. CHARGING OPERATOR - P.A. 0. CHARGING OPERATOR - PASTE E. CHARGING OPERATOR - LATEX r. CHARGING OPERATOR - PLASTIC G. BOARD/CONSOLE OPERATOR H. DLORLOCN OPERATOR I. PROCESS CONTROL OPERATOR 4, 30, 131 1, 13, UJ 111 131 131 131 1. 131. 149 30, 13} 131 130 133 13S 139 A rank ordered exposure rating system requires specific knowledge of all potentially hazardous agents or activities found within the occupational environment. The rank ordered approach to exposure Is preferred because all agents are not always monitorable, nor Is the monitoring of a few agents necessarily adequate In determining the overall occupational risks. Those agents which can be monitored provide additional data which can be Incor porated within the rank ordering system, whether such monitoring Is on an individual, job, or location basis* In this fashion, Interactions between various agents and chemicals can be accounted for. An occupational health surveillance system utilizing a six-point rank ordered scale applied to 22 chemicals (selected for their hepatic toxicity and carcinogenicity) has been applied to a vinyl monomer and synthetic rubber monomer plant; it has been \ shown effective in Identifying relationships between chemical exposure and cancer development [10]. A medical illness and disease data base requires systematic recording of all medical illnesses (1.e. greater than three days) and diseases which re quire medical attention or hospitalization. The medical data should be recorded using the International classification of disease code to allow agreement between companies and occupations regarding the description of diseases or Illnesses which occur. Medical Surveillance Program Level II The MSP Incorporates all the components of the ESP In addition to a peri odic medical examination and limited but specific laboratory screening studies. The medical examination Includes a basic history and physical. There must be uniformity In the history and physical data collected if this Information Is to be effective In Identifying developing Illnesses. Studies URL 05323 `-.a--- URL 05324 41 at the University of Louisville using different facilities and methods of examination (plant versus local hospital; licensed physicians versus trained paramedical personnel, etc.) Indicate that examinations by paramedical staff can provide reproducible examinations of high quality, minimizing downtime, and examination and data collection costs without loss of effectiveness In Identifying physical abnormalItles [11], Specific laboratory screening studies are divided Into a) those selected for monitoring body systems most likely to be affected by the suspect agents, and b) the screening tests designed to monitor the functional capability of all body systems independent of the agents or toxic substances being considered. ia1 all Medical Disease Detection and Treatment Program - Level III its ose The MDDTP contains all the components of ESP and MSP and has, in addition, 3r- a multi-system testing program, a diagnostic triage program, and a therapeutic an management protocol for early treatment. aen 1th The MODTP Is needed for those environments which utilize agents or chem 22 icals which are known toxins or carcinogens. In this circumstance the actual ft* occupational risk to humans may or may not be known. It should be presumed fen that a toxic potential Is present and needs to be monitored. This would be nd akin to industrial monitoring for leaks of explosive materials or the break down of a manufacturing process which could cause serious consequences. Be cause of the higher potential for Injury at this level, the medical history of and physical examinations are more specialized and tailored to deal with the e- known toxin or carcinogen. At this point, work exposure histories may be ex oe panded to include Individual or personal monitoring of the known toxic or car ow cinogenic agents. Additional screening studies may also Include radiological of and radioisotopic screening, such as chest x-rays for asbestos exposure, liver-spleen scan for vinyl monomer workers, bone x-rays for lead workers, etc. [12] Furthermore, screening tests are directed toward the assessment of overall organ function rather than solely to detect acute Injury. Since most occupational disease that develops In Industrial areas occurs from chronic 1- low-level exposure, screening tests which Identify acute or severe Injury are ng usually Incapable of detecting subcllnlcal progressive damage to an organ. 1. These latent developments go undetected because there are usually no symptoms is or signs present during this early Injury. Functional studies are far more as sensitive Indicators of small but progressive changes than simple biochemical 7 42 screening tests. Serial testing also provides evidence of progression long before there is clinical evidence of organ Impairment. Medical Evaluation - A Diagnostic Triage System The systematic protocol used for ltv#r Injury in vinyl chloride environ ments can provide a model for other types of organ Injury [13]. It Includes; 1. Identification of persistent false-positive laboratory tests. These would Include normal variations such as Increased alkaline phosphatase In young adults, and the congentlal variations such as congenital Indirect hyper bilirubinemia. 2. The elimination of common non-occupatlonai cause of liver abnormalities. These would Include viral hepatitis, alcoholic liver Injury, drugs, dia betes, hyperlipidemia, obesity, etc. 3. Removal of the Individual from the work environment If the organ system Injury is considered to be occupationally related and monitoring of changes in that organ system. 4. The screening of other Individuals with known similar exposures for sim ilar abnormalities. 5. Upon identification of the causative agent, elimination or reduction of exposure to the lowest possible level, and continued monitoring of the or gan system for changes. 6. Return of workers to the work environment only after exposure to the causative agent has been eliminated or the job environment Is shown to be safe. For further details regarding Implementation of an OHS, see refer ences 9, 13 and 14. Results In the eight years of application of the Occupational Health Surveillance System to an Industrial cohort of approximately 1,200 employees, at least six major observations have been made regarding vinyl chloride-induced disease. 1. Verification of vinyl chloride and other vinyl monomers' role In Induction of hepatic cancer [3, 10]. 2. The characterization of chronic non-mallgnant subcllnical liver disease [4. 11]. 3. The jur 4. The can 5. The lea 6. The usi Additic a) Ass Few for sen IfIclty healthy screeni therefc populat ci 3D i-- CD An VI CO ro ' In an VI standar Fig. 1. liver d vii-'lL r- URL 05326 long vlronles: would young lyper- Ities. . dla- systera sim- * ft of =5 OP- o the to be -efer- % 1 lance it six e. uctlon Isease 43 3. The Identification of early hepatic lesions characteristic of chemical in jury [15, 16], 4. The Inverse relationship between exposure and latency of vinyl chloride cancer Induction [17]. 5. The effectiveness of clinical screening tests In the detection of chem ical ly-lnduced liver injury [18], 6. The separation of non-occupatlonal versus occupational medical disease using dye clearance studies and serum bile acid levels [19, 20]. Additional findings Include: a) Assessment of Screening Tests In Asymptomatic Populations. Few of the commonly available medical tests have been adequately evaluated for sensitivity (the ability to detect correctly all positive cases) and spec ificity (the ability to detect correctly all negative cases) In asymptomatic healthy populations. The majority of medical tests presently used for screening have been evaluated only In 111 populations. It Is necessary, therefore, that a medical surveillance program(s) contain within it control populations for comparison and subsequent test evaluations. * An example of this need Is seen In the comparison of common "liver tests" In an asymptomatic worker cohort. Figure 1 illustrates the sensitivity of standard screening tests In an ill or hospitalized population. 10 -i All Liver Disease 80- Tests Fig. 1. The sensitivity of standard biochemical liver tests* In Identifying liver disease in an asymptomatic population. i 44 Figures 2, 3 a and b Illustrate the same standard tests with regards to their sensitivity In detecting hepatic disease In an asymptomatic population with non-chemical liver disease and chemical liver Injury proven by liver biopsy. PHO& RUBIN ICG Fig. 2. The frequency of standard biochemical liver tests* reflect presence of hepatic disease in chemical workers suspected of having liver disease. * hr Fig. 3. The sensitivity of standard biochemical liver tests In Identifying: a] chemical liver injury In asynptomatic worker cohort. b) nonchemical liver disease In asymptomatic worker cohort. Clearly there 1$ considerable difference regarding these various tests ability to detect liver disease In these populations. Similar type studies are needed* * (S6PT, ALT) alanine aminotransferase, (SCOT, AST) aspartic aminotransferase, (GGT or GGTP) gamma glutamyl transpeptidase, (AP, ALK PHOS) alkaline phos phatase, (ICG) Indocyanine green clearance, 0.5 low, 2.5 medium, 5.0 mg/kg high dose, (SBA) serum bile acids, (ISO) isocitrlc dehygrogenase, (CG) 1 choleglycine, (CCA) conjugates of cholic acid. for all tion. 0 formatio public. b) Asse Fort lateral pleural dence o The high to the no relaf the 2? c C c) Puln r Pulr 63 smok groups: ' cigaret 26 or rr (MET), (FEF 75 to dete tween e strated Is not d) Car Fif cardiac hour pe trlbuti exposur of the Irregul bzeso'" 10 their with y. sence * * \ ylng: IMty eeded * rase,; phos-& 7cg? 45 for all screening tests which are to be applied to an asymptomatic popula tion. Otherwise, screening tests will provide little useful or additional in formation and Incur excessive costs to the Industry and ultimately to the public. b) Assessment of Possible Vinyl Chloride Injury to the Pulmonary System Forty-five individuals In the worker cohort were discovered to have bi lateral mldzonal pleural thickening on routine annual chest x-rays. Lung and pleural biopsies Identified the thickening as fatty scar tissue without evi dence of malignant change. No asbestos material was found In this tissue. The high incidence of smoking among these workers might have some relationship to the bilateral pleural thickening. The thickening, however, seems to have no relationship to the work exposure data and falls to correlate with any of the 22 chemicals studied [21]. c) Pulmonary Function Studies In Exposed Workers Pulmonary function status was studied In HZ' randomly selected workers: 63 smokers, 49 non-smokers. Participants were classified Into four smoking groups: those who had never smoked {29), those who had smoked 14 or fewer clgarettes/day (11), those who smoked 15 to 25/day (52), and those who smoked 26 or more/day (31). Pulmonary function studies Included mid-expiratory time (MET), forced expiratory volume (1 second FEV), forced expiratory flow (FEF 75-85), maximum mid-flow rate (MMFR) and closing volume. The purpose was to determine whether the pulmonary function studies would differentiate be tween exposed and non-exposed workers. No significant differences were demon strated. This preliminary data Indicates that significant pulmonary disease Is not associated with exposure to vinyl chloride. d) Cardiac Studies In Exposed Workers Fifty-two randomly selected participants were studied for evidences of cardiac conduction irregularities (arrhythmias) after Holt monitoring for a 48 hour period. Eleven had recordings with at least one irregularity. The dis tribution of these Irregularities was studied with regard to the cumulative exposure Indices for each of the 22 chemicals. The median cumulative exposure of the subjects with conduction Irregularities was the sane as those without Irregularities. This study had a P value of 0.65. A second analysis was ... 4- 46 performed In the same manner, but Instead of using total cumulative exposure Index* an Index for the most recent period of exposure (the prior year) was used. Analysis by the Mann-Whltney-Hllcoxon. Test provided a P value of 0.57. Both studies again demonstrated no statistical significant relationship between total cumulative exposure ranking and the most recent exposure ranking with regards to the frequency of cardiac abnormalities. e) Program Costs The ESP can be provided for Industry by university health science centers at an approximate Initial cost of $40 - $50 per worker and maintenance cost of $5 - $7 pe year. Although the higher level programs are more expensive, the cost can be controlled for maximum effectiveness by the regular epidemiologi cal study of the worker population at risk. Discussion v* The use of epidemiology Is essential for the identification of hazards within the environment when dealing with humans. Human epidemiological study is necessarily Independent of chemical structure studies, laboratory toxicol ogical, research, or animal toxicological studies--short or long term. Al though most human toxins have been shown to be toxic or carcinogenic In a bacterial or animal system, thus providing a method with high sensitivity for detecting such agents, their specifIclty--the ability to exclude an agent as potentially toxic--Is considerably less. Most laboratory and animal test systems are designed to determine the toxic potential of agents and are not designed to determine actual human risks. Vinyl chloride is a unique illus tration of this. It Is an essential component In the manufacture of plastics, a material of universal necessity. It Is a simple molecule compared to other synthetic compounds. Structural evidence suggests a potential for toxicity because of Its double bond and chlorine molecule. However, anesthetic agents with very similar structural formulas have been used within certain limits to great human benefit. In fact* vinyl chloride was once used briefly as an anesthetic agent In the postwar period. Because of Its cardiac toxicity and explosive characteristics. It was not considered suitable for general medical use. In animal studies, Its toxic potential was considered to be minimal and Its carcinogenic potential was unsuspected. Long-term animal studies did, Sc however. Identify both its chronic liver Injury potential and Its carcino genicity. It should be noted, that although liver cancer was Identified, the * A type of immediate carclnom. of attet mal 1gnan< spective only beg other th humans o chloride though t sarcoma shortly liver an attrlbut* to the r Epldemio anglosart measures o V7 fC\JO This CO 'tectlng that epii be effect The i the expei cal appl envlronmt is implei Interfen epldemio fy and cl the humai of Inter of healtl dustry ar i -\* v,1 was 57. hip ing ers of the 31- : n- rds udy ol- .r n- f^a 'or as ;St iOt ss, ler ity nts to an and :al and Id, ' 10- the 47 type of liver cancer produced was so rare a variety that It attracted Immediate attention. If vinyl chloride exposure had produced hepatocellular carcinomas rather than angiosarcomas, It may not have received the same degree of attention. In addition, vinyl chloride may be the source *of--oiher malignancies in the lymphatic system, brain, lung and kidney In man. Retro spective studies of human populations exposed to vinyl chloride, however, have only begun to analyze vinyl chloride's causal relationship to malignancies other than liver angiosarcoma. Even now, eight years after the discovery In humans of liver angiosarcoma, there remains a question as to what role vinyl chloride plays In the development of lymphatic, lung and brain tumors. Al though there has been a narked reduction In the occurrence of liver angio sarcoma In vinyl chloride workers throughout the world, this reduction began shortly after the Initial discovery. Considering that vinyl chlorldelnduced liver angiosarcoma has a 10-or-more year latency period, it 1$ Impossible to attribute the repld decrease In the occurrences of liver angiosarcomas solely to the reduction In the exposure level that occurred In the post 1974 era. Epidemiological data Increasingly supports the Idea that the decrease in angiosarcoma cases occurred too soon to have been Influenced by the corrective measures Instituted In 1974 alone [22]. This observation highlights the need for a more effective system of de tecting such occupationally-induced diseases. It is, therefore, essential that epidemiological methodology be applied prospectively If prevention is to be effective and meaningful. Summary The Occupational Health Surveillance System described herein has provided the experience and data to clearly demonstrate that prospective, epidemiologi cal application to the problem of health surveillance In the occupational environment Is feasible and economical. It has demonstrated that the approach is Implementable In Industries of any size or type, can be operated without Interference with industrial productivity. Is extremely cost-effective at the epidemiological surveillance program level, provides the best means to identi fy and characterize agents which may produce occupationally-related disease In the human population, provides an ongoing means of assessing the effectiveness of Intervention or preventive measures and be provided through the expertise of health sciences centers with economic benefit to the universities and In dustry and a significant social benefit to the community. URL 05330 fit* 1 t b 48 Acknowledgements: Portions of this work were supported by National Cancer In stitute Contract # N0-1-CN-55212, the Manufacturing Chemists' Association grant # VC-7, and the 6. F. Goodrich Company. The authors would like to thank Mrs. N.V. Strong for expert manuscript preparation. REFERENCES 1. Trlbukh, S.L., N.P. Tikhomirova, S.V. Levina & L.A. Kozlov. (1949): Glgtena Sanit. 10:38. 2. Wilson, R.H., W.E. McCormick, C.F. Tatur & J.L. Creech. (1967): J. Arru Med. Assoc. 201:577-581. 3. Creech, J.L., Jr. ( M.N, Johnson. (1974): J. Occupational Med. 16:150-151. 4. Creech, J.L., Jr. 6 L. Makk, (1975): ANYAS. 246:88-94. 5. Greenberg, R.A., C.H. Tamburro, l C.E. Kupchella. (1978): Prevention and Detection of Cancer, N.Y.: Part 11, Vol. 2 pp. 1921-1928 (Nelburgs, H. ed.), Marcel Dekker, Inc. 6. Ames, B.N. (1979): Science, 204:587-593. 7. Plenta, R.J., J. A. Polley fc W.8. Lebherz, 111. (1977): Int. J. Cancer, . 19:642-655. 8 Uelsburger, J.H. (1976): Chemical Carcinogens, Searle, C.E. (ed.) ACS Monography 173. American Chemical Society, Washington, D.C. 9. Tamburro, C.H., C.S. Davidson, M.M. Fisher, et al. (1979): Guidelines for Detection of Hepatotoxlclty Due to Drugs and Chemicals. Davidson, C.S., leevy, C.M. fc Chamberlain, E.C. (eds.) U.S. Department of HEW, NIH . Pub. No. 79-313, pp. 60-80. 10 Greenberg, R.A. t C.H. Tamburro. (1981): J. Occupational Med., , 23:353-358. 11 Tamburro, C.H., R.A. Greenberg, L.F. Newby l< D.M. Turns. (1978): Report on Implementation and Assessment of a Demonstration Cancer Control Detec tion and Prevention Program In a Cohort of Industrial Workers. National . Cancer Institute Program Contract N0-1-CN-55212. 12 : Whelan, J.G., Jr., R. Greenberg fc C.H. Tamburro. (1980): Gastro . enterology, 79:1129. 13 Tamburro, C.H. (1979): Medical Clinics North America. 63:545-566. 14. Tamburro, C.H., U.N. Strelps fc J.L. Wong. (1982): Clinical Medicine for the Occupational Physician, pp. 255-296. M.H. Alderman & M.J. Henley (eds.). Marcel Dekker, Inc., New York, New York. 15. .'Tamburro, C.H., J.L. Creech, A, Davis & R.A. Greenberg. .(1978): Gastro enterology 75:969. 16. Tamburro, C.H., L. Makk l> H. Popper. (1979); Gastroenterology 77:A43. 17, Tamburro, C.H. & R.A. Greenberg. (1982): Hepatology 2:149. 18, Tamburro, C.H. I* R.A. 6reenburg. (1981): Environmental Perspectives, ..~-7 19 20 <?21. _^22. 41:117-122. Liss, G. & C.H. Tamburro. (1982): The Pharmacologist. 24:247. L1s$, G. & C.H. Tamburro. (1982): Hepatology. 2:692. Tamburro, C.H. (1976): Texas Reports on Biology & Medicine. 37:126-144. Tamburro, C.H. fc R.A. Greenberg. (1982): Clinical Research. 30:307A. e* veey n u o