Document 3eZwoyq6XnD5mJnGgQbDXExdx

5 Environmental Health Perspective* Vnl, it, pp. 117-122, mi Effectiveness of Federally Required Medical Laboratory Screening in the Detection of Chemical Liver Injury by Carlo H. Tamburro* and Richard Greenberg* The increasing concern of industrialized societies over the potential health hazard of synthetic chemicals in the occupational environment has led to goverment requirements for medical laboratory screening of workers. The specific tests for such screening programs are most often selected on the basis of medical experience which utilized them in symptomatic or hospitalized populations. Required screening tests for hepatic injury including cancer in vinyl chloride workers has been systematically and prospectively studied in an industrial population working with synthetic rubber and plastics. Approximately 1300 employees were studied over a five-year period. A cohort of %9 male employees, fur the purposes of analysis, were divided into a "standard" and "nonstandard" population based upon the absence or presence of significant medical disease (including liver disease). A subcohort of 120 individuals was further identified based on availahiliity of liver biopsy. Evaluation of federally required studies included alkaline phosphatase (AIM, y-glutamyl tmnspcptidase (GGT1M, alanine antinntrunscrase (ALT. SG!*T), aspartic aminotninsfcmse (AST, SHOT) and bilirubin (lilt). Also studied were indocyanine green clearance (lUiliind nidioisotopic liver spleen scans (L-S scans). The GGTI* provided the highest positive predicted value us a screening lest for identifying "nonstandard" individuals (individuals with ail types of medical disease) followed by ICG. AST, ALT. L-S scan, Al*, and BR. In the identification of asymptomntic liver disease the GGTI* had the least specificity due to a high false positive rate, while the Al* provided the highest specificity. The ICG clearance however, provided the best combination of positive predictive value and sum of specificity and sensitivity. The Al* provided additional increase in specificity as-a follow-up study. There was no evidence that any of the other federally required tests added any additional benefit and did add significant increase in the false positive rate. These studies support the need for evaluating screening tests as to their sensitivity, specificity and positive predictive value, in asymptomatic individuals, before they are made established requirements. Introduction Industrialized societies throughout the world have become increasingly concerned over the poten tial health hazard of synthetic chemicals in the occupational environment. Governmental regula tions have increased the number and types of medical laboratory screening required for a large variety of halogenated hydrocarbons as well as other potential environmental hazards. The pri mary objective of these screening programs is to "Liver Research Center. Division of Digestive Diseases. Department of Medicine, and Department of Community Health and Cancer Center, University of Louisville School of Medicine, Louisville, Kentucky 40201, October 1981 reduce disability, morbidity and mortality in work ers, especially as related to serious low-grade health hazards. In general, screening programs are instituted because of the presence in the work environment of a suspected or proven environmen tal toxin or carcinogen, which has the potential of producing low-grade injury over long periods of exposure. Most screening studies are directed toward the detection of abnormalities in certain body systems. The specific tests are frequently selected on the basis of medical experience which utilized them in symptomatic or hospitalized populations. Prior expe riences utilizing nonspecific multiphasie health sur veillance screening and maintenance have not proven to be cost effective except under certain limited 117 I conditions (1). The cost effectiveness of such tests, however, in the determination of medical screening requirements, has played a limited role due to the potential seriousness of these occupational agents. Little attention has been paid as to whether the effectiveness of federally required screening pro vides the best or, more importantly, a necessary benefit when applied to asymptomatic and other wise healthy worker populations. The discovery in 1974 of hepatic toxicity and cancer formation in vinyl chloride workers provided the opportunity to systematically and prospectively study the effectiveness of federally required and federally recommended medical screening proce dures for the detection of. chemical liver injury, including cancer development (2). Table 1 lists the federally required medical screening procedures since 1974 for environments utilizing vinyl chloride or polyvinyl chloride. Table 2 lists the federally recommended studies for these same environments.' This paper will present a preliminary assessment of the effectiveness of these federally required studies in the accurate detection and identification of chem ically induced liver injury due to halogenated hydro carbons, especially vinyl chloride. Materials and Methods The industrial population studied consisted of approximately 1200-1400 employees of a chemical plant whose two major products were synthetic rubber and plastics. The industrial plant had been in operation for over 35 years and had a predomi nance of male employees (96%), approximately 80-87% of the work force being white, 11-12% black, less than 1% of other racial origins. Turnover of the plant was approximately 10 to 15% per year with 65-70% of the work force having worked five years or more at the plant. Employee ages ranged from 18-65, with a mean of 52 years. A cohort consisting of 969 male employees who worked continually from June 1, 1976 to May 31. 1977 was, for purposes of this analysis, divided into a "standard" and a "nonstandard" population. These designations were given on the basis of a review of Table 1. Federally required studies for vinyl chloride workers. History and physical < 10 years as vinyl chloride worker--(annual) > 10 years as vinyl chloride worker--(semiannual) Biochemical studies SGOT (AST) SGPT (ALT) GGTP AP TB 118 Table 2. Federally recommi tided (not required) studies. Hepatic studies LDH Isoenzyme Total protein Protein electrophoresis HMp . Radioisotopic scan Kidney dysfunction (urine examination) Albumin RBC Exfoliative abnormal cells Pulmonary system FVC FEV, Chest x-ray (PA and lateral) all present standard medical data on each employ ee, including the federally required studies. Other screening studies of the medical surveillance pro grams were not utilized in the classification of overall medical status because, at that time, their clinical usefulness was unknown or controversial. All studies were performed on an annual basis; those individuals with ten years or more of employ ment were examined and screened semiannually. Compliance with medical screening studies during the five-year study period showed a continuous participation in the history and physical examina tions by over 75% of the work force, laboratory tests and chest x-rays by 86%, and liver-spleen scans by 85%. Seventeen percent failed to undergo at least one history and physical examination, 9% did not have any of the radiological studies, -and only 4% failed to have laboratory studies durihglhis period. Approximately 40-50% of these individuals who did not undergo an examination claimed to have been examined by their private physician. A subcohort of 120 individuals was further identified based on the availability of a liver biopsy performed for medical reasons, both related and not related to their work. The term "standard" is used for those individuals who, based upon the best medical opinion, demon strated no evidence of any significant medical disease, occupational or nonoccupational in origin. The "nonstandard" population included all others not included in the standard population. The subcohort population was divided into those individuals with and without histological evidence of liver injury and further subdivided into those with and without histological features characteris tic of chemical injury. All employees had individual work histories. These consisted of a standardized job classification for ail jobs within the plant since its opening and a Environmental Health Perspectives I 1 :!i 30 fio (/) OJ to -J j fit i. i i I- i 11: ?. S. * l rank ordering of exposure for 22 different sus pected or potentially hazardous heptatoxic chemi cals used within the work place (3-5). The agents were rank ordered on the basis of the intensity of exposure for each of the job classifications for each of the years that the plant was in operation. From this detailed work history, a cumulative exposure ran month ration (CEKM) was determined for each employee for each of the 22 chemicals. All histologi cal material was classified as to the presence or absence of liver disease, and to whether the abnor malities were consistent with chemical or non chemical ipjury. This classification was conducted double blindly by three experienced physicians, two pathologists, and a hepatologist (ff), without knowledge of any medical data, exposure or work history. Results Although 50 or more biochemical screening tests were performed during this study period, this paper will limit itself to the evaluation of the federally required studies, the indocyanine green clearance (ICG) study at the 0.5 mg/kg dose (7, 8) and radioisotopic liver and spleen scan {9). The GGTP ICG SGOT 0.S AST SGPT LIVER SPLEEN ALT SIZE TESTS Figure 1. Positive predictive values of screening tests in identification of medical disease in an asymptomatic working population (N 969). All those screening tests with positive predictive values of greater than 70 are shown except for indirect bilirubin (due to high number of congenital indirect hyperbilirubinemia) and trigiyceride determination. Above each bar in the graph are shown the sum values for sensitivity and specificity of each test. They generally follow the same ranking. October 1981 SGPT GGT AIK SGOT ICD BIL1* Q5mg50mg PHOS RUBIN ICG * Figure 2. Frequency with which clinical biochemical tests cor rectly reflex the presence of hepatic damage in chemical workers suspected of having liver disease*. (SGPT) alanine aminotransferase (ALT) (GGT) -y-glutamyl transpeptidase, (SCOT) aspartic aminotransferase (AST). (Aik. Phos.) alka line phosphatase, (ICD) isocitnc dehydrogenase (ICG) Indo cyanine Green clearances at 0.5 and 5.0 mg/kg dose. i y federally required biochemical studies include alka line phosphatase (AP), y-glutamyl transpeptidase (GGPT), alanine aminotransferase (ALT/SGPT), bilirubin (ALT/SGPT), and the aspartic amino transferase (AST/SGOT). The positive predictive values of these screening tests in identifying medical disease (including Iiveij^^ disease) in this asymptomatic working populations^ are shown in Figure 1. The GGTP provided the highest positive predictive value as a screening test for "nonstandard" individuals. It also provided the highest sensitivity and specificity sum shown in brackets. The predictive value of the other tests, in decreasing positivity were ICG, AST, ALT, liver and spleen scan, AP, and bilirubin. Further evaluations were conducted on the subcohort population in whom we had both histolog ical and biochemical data concerning hepatocellular damage. If one looks at only those individuals who received liver biopsies for suspected liver disease then one would find the percent of positive tests as illustrated in Figure 2. The ALT (SGPT), GGTP, AP and AST (SGOT) demonstrate a very high degree of sensitivity in identifying individuals with hepatic disease. As shown on the right, ICG clearances at the 0.5 mg/kg level provide a similar degree of sensitivity to SGOT and AP. The higher dose ICG clearance (5 mg/kg) appears to provide the most sensitivity for latent hepatic disease. These findings are consistent with the general medical experience with hospitalized patients. Sensitivity alone however is not an adequate indicator of a test's screening value, especially when used in asymptomatic individuals. More appro priate evaluation of these tests' value as screening n^Pinstruments are shown by their sensitivity, specificit)^ T .1 R&S 116428 R&S 116429 saas mu-'c CLl CHEMICAL LlVCK MUuRY LQ* Livet OlftCASt ANDAAO * MOAN 60 ,, AV19A6C vc ci^osune i 2i4 vatimos Figure 3. Sensitivity and specificity of various biochemical screening tests and their sensitivity and specificity sum values (S & S) based on 78 with biopsy documentation oftheir hepatic status and all of the biochemical screening studies listed. All screening tests with S & S sums less than 110 (e.g. bilirubin and isocitric dehydrogenase, are not illustrated. CCI to so CROUP RATINGS Figure 4. Correlation between the histologic findings on liver biopsy and each individual's average total vinyl chloride exposure based on their average CERM (Cumulative Expo sure Rank Months) ratings. Rankings: 1 = lowest possible exposure: 2 3 minimal exposure, low levels; 3 moderate exposure; 4 worked in areas subject to occasional high excursions, or frequently high and/or had intimate contact and sum values shown in Figure 3 in the biopsied subpopulation. Here again, -y-glutamyl transpeptidase and ICG clearance (0.5 mg dose) show the greatest sensitivity for identifying individuals with liver disease. However, GGPT had the least specificity, reflecting its high incidence of false positives. Specificity increased with the use of AST, ALT, and ICG clearance. The alkaline phosphatase pro vided the highest specificity, suggesting that mild or low grade chronic hepatic injury due to environ mental agents may be activating hepatic AP syn thesis in the absence of biliary tract obstruction or cholestasis. The ICG clearances, even at the low dose (0.5 mg/kg), clearly remains the test with the best combined sensitive and specific screening study for detection of individuals with subclinical hepatic disease. This subcohort biopsied group was further exam ined on the basis of the histological interpretation of their liver biopsies and their work exposure to vinyl chloride. All biopsied individuals were subdivided into three groups: 19 with histological evidence consistent with chemical liver injury; 30 with histo logical evidence of liver disease, nonchemical liver injury; and 29 with normal liver biopsies. Each of the histological subgroups were further subdivided based on their vinyl chloride exposure, on a scale of 1 to 4 (Fig. 4). The chemical liver injury group contained the highest percentage of individuals with the highest average rating (CERM) for vinyl chloride expo sure. In contrast, with those with liver disease, nonchemicai, and those with normal livers have a 120 more even distribution of individuals relative to their degrees of vinyl chloride exposure. In our previous studies we noted that almost all individuals with histologically specific lesion of vinyl chloride injury or angiosarcoma had a total average CERM rating of 3.5 or greater. The asterisk in Figure 3 indicates the percentage of individuals in each of the three histological groups with exposure ratings of 3.5 or greater. Again, the chemical liver injury group have the highest per centage of individuals with the high exposure ratmgsrThis further supports previous work U, 10) identifying focal hepatocellular hyperplasia as the earliest histological characteristics of chemical injury in liver disease. A study of the frequency with which these tests are positive among those individuals with liver disease, based on their histological findings (chem ical versus nonchemical), provides additional data supporting the clinical observation that an increased AP has a greater specificity for chronic liver injury. Figure 5 shows the ratio of the proportion of positive screening tests in those with histological chemical liver disease divided by the proportion of positive tests in those whose disease is not of chemical origin. All tests, independent of their sensitivity and specificity for liver injury, were more frequently abnormal in the presence of nonchemical, subclinical liver injury, except for AP. In contrast, AP was far more frequently abnormal in those individuals with chemical liver injury, which tended to be more chronic than acute and generally less severe. Environmental Health Perspectives A J best means of developing effective triage protocols for the screening program. For example, in this particular population of industrial workers, we have shown that the assessment of hepatic function is best accomplished by low dose ICG clearance (0.5 mg/kg). The ICG clearance is somewhat a more complicated technique (i.e., injection of substance and repeated blood sampling) but requires only 10 min to perform, and needs only one needle stick. In exchange it provides the best singular screening test for latent hepatic injury. If adequate medical facilities are not easily accessible, then ALT should be substituted. If either ICG clearance and/or ALT studies are found to be abnormal, an AP should be done and a diagnostic work-up instituted to deter mine the etiology (12). The rationale for these recommendations is based on the actual study of chronic subacute chemical iqjury in an asymptomatic population, not preselected because of signs or symptoms. Therefore the test's TESTS ability to correctly differentiate disease from nondisease or one type of injury from another is Figure 5. Frequency with which biochemical testa were abnor mal in those with different type of hepatic injury cxprcaxeii as a ratio: (CL1) chemical liver injury, (LI)) liver diiunuic, nonchemical. more accurately determined. Chemical and envi ronmental agents of low toxicity tend to produce repeated or persistent injury which accumulates- over time. Tests which measure overall functional capacity quantitatively or semiquantitatively, rath^^ than measuring acute low-grade injury over tin^P Discussion are more likely to detect changes. For this reason, clearance or tolerance studies provide the best This preliminary systematic review of the posi tive predictive values and the sensitivity and means for identifying latent hepatic disease, while enzyme studies like ALT, GGFT, and SGOT usu specificity of federally and some non-federally ally reflect acute cellular injury of higher grade or required tests for chemical workers provides the degree and cannot accurately reflex accumulative first scientific and biological basis for the selection damage until very late in the disease process. Tests 30 So C/5 of medical screening tests for liver injury in occupa tional environments. Although these commonly used medical tests have been found by clinical which provide information concerning the progres sion or nonprogression of injury will be far more helpful to the practicing occupational physician. experience to be effective as diagnostic tools in the They provide him/her with a better capability to symptomatically ill or hospitalized population, little discern between nonoccupational and occupational O) clinical work has been done to determine their disease, and the best available reassurance for the -fe oCO ability to accurately separate biological variations worker of his or her safety while allowing the from early latent or underlying disease in asymp greatest possibility for continued productivity and tomatic individuals. Tests which provide very high employment. false-positive rates (decreased specificity) such as Finally, these data provide a sound scientific GGTF, interfere with the screening process identi basis upon which to modify federal requirements. fication of the high risk worker by the extra time The removal of specific testing requirements which, and cost required for repeat testing, the decreased with field experience, prove not to have any significant productivity for the employer, the employees' positive predictive value, or effective sensitivity increased anxiety, and by the loss of confidence in and specificity will aid in reducing overall cost and the effectiveness of the testing procr-rim by both employees and employer. Detem:nation of the sensitivity and specificity of screening studies for asymptomatic individuals is essential if effective recommendations are to be made a federal require ment. This evaluation process also provided the help maintain continued compliance by industry and workers. There may be theoretical reasons to maintain or continue some of the present federally required screening studies, but these reasons should be separately identified and not be confused with the purposes of the more effective test in October 1981 vMSi-Vi.W detection of occupationally related liver injury. The capabilities and limitations of any new tests or old tests for new screening purposes in detection of other potential occupational hazards, should be validated before making them a required screening procedure. This would lay the foundation for sys tematic determination of effectiveness of screening procedure against a proven standard. Unvalidated federal requirements provide the worker and employer with a false sense of security and safety by what is believed to be effective monitoring. More importantly, such a situation can lead to delay in effective correction of cause and disease preven tion. Conclusions Biochemical screening for hepatic injury in asymp tomatic chemical workers can be done most effec tively by the use of liver specific clearance studies. ICG clearance provides the best combination of " positive predictive value and sensitivity and specificity .for functional hepatic testing at the present time. , None of the present federally required studies provide any significant degree of sensitivity with out marked reduction in specificity in asymptomatic individuals. The ALT (SGOT) is the most useful among those Federal tests presently required and the alkaline phosphatase may provide additional specificity as a follow-up study in those individuals with positive ICG or ALT screening studies. There is no evidence that any of the other federal studies add any benefit and strong evidence that they significantly increase the false-positive results in well individuals. All screening studies should undergo evaluation as to their positive predictive value and sensitivity and specificity in asymptomatic individuals before becoming permanent or established requirements. Portions of this work were supported by National Cancer Institute Contract No-l-CN-55212 and Manufacturing Chem ists Association Grant. The authors wish to acknowledge the help and cooperation of Hynson, Westcott & Dunning and B. F. Goodrich Chemical Company. , REFERENCES 1. Collen, M. F. Cost effectiveness of multiphasic health testing services. In: Multiphasic Health Testing Services, M. F. Collen, Ed.. Wiley. New York, 1978, Chapter 17. Section F, pp. 487-530. 2. Creech, J. L., Makk, L., Whelan, J. G., Jr., and Tamburro. C. H. Hepatotoxicity among polyvinyl chloride production workers during first year of surveillance program. Gastro enterology 67: 786 (1974). 3. Greenberg, R. A., Tamburro, C, H.. and Kupchella, E. C. Prospective medical surveillance program for detection and prevention of industrial related cancer. In: Prevention and Detection of Cancer Part 1, Voi. 2; H. Nteburgs, Ed., Marcel Dekker. New York, 1978, pp. 1921-28. 4. Tamburro, C. H., Greenberg, R. A., Newby, L. G., and Turns, D. M. Implementation and assessment of a demon stration cancer control detection and prevention program in a cohort of industrial workers. Program Contract #N01CN-55212 Final Report. Division of Cancer Control and Rehabilitation, National Cancer Institute, Bethesda, Mary land, 1978. 5. Greenberg, R. A., and Tamburro, C. H. Exposure indices for epidemiological surveillance of carcinogenic agents in an industrial chemical environment. J. Occup. Med., in press. 6. Tamburro, C. H., Makk, L., and Popper, H. Early hepatic histological alterations among chemical (vinyl monomer) workers. Gastroenterology 77: A33 (November 1979). 7. Fortwengler, P,, and Tamburro, C. H. Use of dye clearance in the detection of hepatocellular injury among vmyl chlo ride workers. Clin. Res. 23: 264A (1975). 8. Tamburro, C. H., Creech, J, L, Davis, A., and Greenberg, R. A. Indocyanine green clearance as a prospective indica tor of hepatocellular chemical toxicity. Gastroenterology 75; 989 (1978k------- 9. Whelan, J. G., Jr., Greenberg, R., and Tamburro, C. H. Radioisotopic scans and gray scale ultrasonography in detection of liver damage. Gastroenterology 79:1129 (1980). 10. Popper, H. and Thomas, L. B. Alterations of liver and spleen among workers exposed to vinyl chloride. Ann. N. Y. Acad. Sci. 246: 172 (1976). 11. Tamburro, C. H. Chemical hepatitis, pathogenesis, detec tion and management. Med. Clin. N- Amer. 63: 546 (1979). 122 Environmental Health Perspectives