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J. Soc. Occup. Med. (1991) 41, 10- 16 Sr-f*
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Persistent Liver Dysfunction among Workers at a Vinyl Chloride Monomer Polymerization Plant
S. F. HO, W. H. PHOON. S. L. GAN and Y. K. CHAN
,Department of Industrial Health Ministry of Labour, Singapore
Summary
Thirteen workers with persistent abnormalities in one or more liver function tests (LFT) at a vinyl chloride monomer (VCM) polymerization plant were investigated.
Twelve workers were found to have VCM-induccd liver dysfunction based on circumstantial evidence. They were employed between 1971 and 1982 when the VCM levels ranged from 1 to 21 p.p.m. After 1982 when the environmental VCM levels were controlled to below I p.p.m., no cases of VCM-induced liver dysfunction were detected. In most cases, glutamic pyruvic transaminase was the earliest parameter to be raised. The second most common parameter is serum gamma glutamyl transpeptidase. The latent period ranged from 1 to 13 years. An improvement in their LFT results was shown by 83.3 per cent of workers within 6 months to 2 years after removal from further VCM exposure. For workers who returned to VCM work, their LFT became abnormal again. Liver scans showed hepato and/or splenomegaly in most cases. Liver biopsies on 9 workers were reported as `non-specific fatty changes' of varying degrees.
These observations highlight the need for continual vigilance with environmental monitoring and medical surveillance of VCM-exposed workers.
Introduction
The detection of hepatic angiosarcoma among workers in a vinyl chloride polymerization plant in the United States1 led rapidly to surveys of workers in such factories2,3. Since then, industrialized countries throughout the world have become increasingly concerned over the potential health effects of vinyl chloride monomer (VCM). This paper presents the findings on 13 workers with persistent liver dysfunction detected during a medical surveillance programme at a VCM polymerization plant and proposes a systematic plan of investigation.
Materials and Method
A VCM plant was set up in Singapore in the early 1970s to produce polyvinyl chloride (PVC) powder by the polymerization of VCM.
Medical examination for workers at this plant started in 1975 on a voluntary basis. Tests were done to look for evidence of liver disease. These tests comprised the biochemical liver function tests (LFT): serum bilirubin, serum alkaline phosphatase (AP), serum gamma glutamyl transpeptidase (GGT) and the transaminases, serum glutamic oxaloacetic transaminase (GOT) and serum glutamic pyruvic transaminase (GPT). If the initial LFT was normal, similar tests would be repeated annually. If there was one or more abnormalities, the abnormal test(s) would be repeated in 3 months after advising the worker to abstain from alcohol. If the abnormality persisted, the worker would be required to undergo a comprehensive physical examination including biochemical tests such as carcino-embryonic antigen (CEA), alpha foeto-protein (AFP), hepatitis B antigen (HBsAg) and a technetium99m liver colloid scan. However, this surveillance
programme was not carried out systematically nor was there proper supervision. Liver function tests were analysed at 3 different laboratories. However, the type of LFT abnormality reported was fairly consistent among the 3 laboratories. All these were later rectified by 1983.
All workers who had persistent abnormalities (on at least 1 repeat test) in one or more LFT and with I or more years of exposure formed the basis of this report. A detailed occupational, medical and alcohol history was obtained from each worker. A complete physical examination with special attention to the liver, spleen, skin and extremities was done. The laboratory tests included technetium-99m liver colloid scan, HBsAg, CEA and AFP. The latter 3 were done by radioimmunoassay method. Liver biopsy was only done on 9 workers who were still with the plant at the time of this review. The specimens were read by 2 pathologists independently.
Environmental assessments comprising area and personal sampling were carried out on a periodic basis at different sections of the plant. Area sampling had been carried out at monthly intervals since 1976 by the company's safety officer using Kitagawa detector tubes and a photo-ioniser (HNU model P101).
Personal sampling was started in 1983 by our department, using 3M organic vapour monitors. Sampling duration was about 5-7 hours. The samples were analysed by carbon disulphide desorption and gas chromatography in accordance with the NIOSH Method No: P & CAM 178.
The results of the medical and environmental monitoring are discussed in this report.
Results
The Plant The VCM was purified before it was charged into reactors containing de-ionized water and peroxidase initiators. The reaction took place in batches in the 6 autoclaves (reactors) to produce PVC slurry. At the end of the polymerization, the unreacted VCM was recovered by evacuation. The PVC slurry was further stripped of VCM before it was centrifuged to remove the water to produce PVC powder. The PVC powder was then packed and supplied to other factories where it would be used for the manufacture of PVC pipes, resins, etc. Our 13 workers came from various sections of the plant.
Exposure to vinyl chloride monomer The highest exposure occurred during reactor cleaning. Here, workers were required to enter the reactors to clean
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experienced nausea especially during the washing of the slurry tank. Three had loss of appetite while 2 had complaints of weight loss. Worker F had all of the above symptoms. Table II summarizes the clinical findings and investigation results of the individual workers....
'On examination, all were well built and clinically well. None had any jaundice, hepatosplenomegaly or signs of liver disease, sclerodermatous skin changes or aeroosteolysis.
Hepatitis B antigen, carcino-embryonic antigen and
alpha foetoprotein were not present in all 13 workers.
Serial Lit;er Function Test Results Table III gives the serial LFT results. Of the 13 workers investigated, 3 workers had only one persistent LFT abnormality, 2 had 2 abnormalities and 8 had 3 or more abnormalities in the battery of tests.
WORKERS WITH ONE LFT ABNORMALITY
Workers A and B had raised bilirubin and worker C had raised GPT. Workers A and B were confirmed to have benign unconjugated hyperbilirubinaemia (Gilbert's syndrome). Their bilirubin levels fluctuated from 1.4 to 2.6 mg/100 ml and remained so even after removal from VCM exposure.
Worker C's serum GPT level became normal after removal from VCM exposure and was raised again on return to VCM work. These findings support the diagnosis of VCM-induced liver dysfunction.
WORKERS WITH TWO LFT ABNORMALITIES
Workers D and E had raised GPT and GGT levels, and GPT and GOT levels respectively. They worked in the polymerization section and their LFT improved when they were removed from VCM exposure. However, their LFT became abnormal within a year of returning to VCM work. As alcohol and viral hepatitis were already excluded as possible causes, these findings were consistent with the diagnosis of VCM-induced liver dysfunction.
WORKERS WITH THREE OR MORE LFT ABNORMALITIES
Eight workers had 3 or more abnormal LFT results. All except M (there were no previous LFT results for comparison) had normal LFT results prior to the development of the persistent abnormalities. These abnormalities developed within 1 to 7 years of starting work (mean 4.5 years).
Three workers showed an improvement in their LFT results within 6 months of removal from VCM exposure and in workers G and K, the results returned to normal. These 2 workers were removed from further VCM exposure within one and a half years of developing the abnormal LFT result. Workers G and M who returned to VCM work re-developed abnormal LFT results. These findings supported the diagnosis of VCM-induced liver dysfunction. In addition, M had diabetes mellitus which was controlled with insulin injections.
The remaining 5 workers had fluctuations in their LFT results. Workers F, H and 1 were in the maintenance section where the exposure to VCM varied depending on the type and place of work. This may account for the fluctuation in their LFT results. However, where there was documented removal from VCM exposure, their LFT results improved suggesting that they probably had VCM-induced liver dysfunction. In the case ofL, we could
13LIVER DYSf-UNCTION AND A VCM POLYMER PLANT
not explain the fluctuation in the LFT results, although there was definite improvement when he was removed from further VCM exposure. He probably had VCMinduced liver dysfunction. Worker J had a history of drinking about a bottle of brandy/whisky and 3-4 bottles of toddy at least once a week for the last 20 years. His LFT results fluctuated probably with variation in his drinking habits. There was also no improvement in the results after removal from further VCM exposure, thus suggesting that alcoholic liver cirrhosis was the most probable cause of his persistent liver dysfunction. He also had diabetes mellitus which was well controlled by tolbutamide.
h
Liver Scan Results
Four workers had hepatomegaly and four had hepato splenomegaly. Two workers had only splenomegaly. The rest had norma] liver scans. Enlargement of the liver and spleen was based on an enlargement of 2 cm or more when compared to the normal spans for liver (15 cm) and spleen (8 cm) in our local population.
Biopsy Findings
Liver biopsies were carried out on 9 workers. The liver tissues showed normal lobular architecture. There were mild to moderate fatty changes. Portal tracts were normal except slightly widened by aggregates of chronic inflammatory cells in the case of worker C. In 3 cases, there were aggregates of mononuclear cells among the fat vacuoles. Ktipfier cells appeared active in 3 cases. Sinusoidal dilatation was present in worker I and in workers B and D, the hepatocytes displayed megalocytosis with enlarged darkly stained nuclei. No malignant change was observed. The histological diagnosis was non-specific fatty changes of varying degrees although none was obese clinically, 3 were ex-drinkers, 2 were teetotallers and the rest were social drinkers.
Diagnosis
For the 9 workers who had liver biopsies, three had VCM-induced liver dysfunction and 4 were probable cases as explained earlier. The remaining 2 were confirmed as having Gilbert's syndrome. In addition, they probably had VCM-induced liver dysfunction in view of the abnormal liver scan and biopsy reports which could not be explained by Gilbert's syndrome alone.
Hence, of the 13 workers with persistent liver dysfunction, 6 were caused by exposure to VCM (1 had in addition diabetes mellitus), 6 were probably VCM-induced (2 had in addition Gilbert's syndrome) and 1 had alcoholic liver cirrhosis with diabetes mellitus.
Discussion
Our study showed 13 (4.8 per cent) workers with persistent liver dysfunction. Of these, 12 workers had VCM-induced liver dysfunction (6 possible and 6 probable cases) based on circumstantial evidence and after excluding alcohol and viral hepatitis as possible causes. The discussion centres on these 12 cases.
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Table III. Follnw-up liver function lest results in 13 workers exposed to vinyl chloride monomer polymerization
H'ofki-r
Year of first abnormal result
First ahiuirmal result
Serial abnormal liver function test results
A
1984
Bil
Before 81 NA
Jul 81 Normal
Jul 82 Normal
Aug 83 Normal
Jul 84 Bil
Ocl 84 Norma]
Jan 86 Normal
May 86 Bil*
Jun 86 Bil
Oct 86 Bil
Feb 87 Bil
B
1978
Bit
Before
Aug 78 Sep 78
Mar 79
Ocl 79
Aug 80 Jul 81
Oct 81 Jun 82 Aug 83
Jul 84
May 85 Jan 66 Jun 86 Oct 86 Feb 87
78
NA
Bil Bil
Bil
Bil
Normal Bil
Normal Normal Ril
r 1981
OPT
Before
Aug 83 Apr 84
Jul 84
Oct 84
Jun 85
Normal Bil
Bil* Bil
Bil
Bit
83
NA
GPT*
Normal** GPT
GPT
Resigned
D
1984
GGT
Before
Aug 77 Sep 78
Oct 79
Aug 80
Aug 81 Jul 82
Jul 84
Oct 84 May 85
Jun 86 Oct 86 Jul 87
77
NA
Normal Normal
Normal
Normal
Normal Normal GGT
GGT*
Normal** GOT
GGT
GGT
GPT
GPT
GPT
E
1981
GOT
Before
Jul 81
Jul 82
Aug 83
Apr 84
Jul 84 May 85 Jan 86 Mar 86 Jun 86
Jul 87; Died of cerbrovascular accident after a fall at home.
8!
NA
Normal Normal
GOT*
Normal** Normal GPT
GPT
GPT
GPT*
`
F
1980
GPT
Before
80
NA
Oct 80 GPT
Mar 81 Normal
Jul 82 Normal
Mar 8) Jul 84
Normal GPT GGT
GOT Oct 84
GPT GGT GOT
Apr 85
GPT GGT GOT
May 85
GPT* GGT
Sep 85
GPT GGT GPT
Ocl 85 GPT**
Mar 86
GPT GGT GOT
Aug 66
GPT GGT
Jan 87
GPT* GGT GOT
Apr 87
GPT GGT GOT
Resigned
G
1983
GPT
Before
Aug 82 Aug 83
Mar 84
Aug 84
Nov 84 May 85 Oct 86 Oct 87
GOT
NA
Normal GPT*
Normal** GGT
GPT* Normal Normal Normal
GOT
GGT
II 1980
GPT
Before
Aug 77 Sep 78
Oct 79
Aug 80
Oct 80 Feb 81 Jul 8!
Oct 81 Jul 82 .
Sep 82 Jut 84 Oct 84 Jan 8$ May 85 Oct 85 Jan 86 Jun 86 Jan 87
77
GOT
NA
Normal Normal
Normal
GPT*
GPT4* GPT
GGT
Normal GPT
Normal GPT
GGT
GPT
GPT
GPT GPT
GPT
GPT
GGT
GGT
GGT
GGT
GGT
GGT GOT
GGT
GGT
GOT
I 1980
GPT
Before
Oct 79 Aug 80
Ocl 80
Feb Ml
Jul 81
Jul 82
Sep 82 Aug 83 Jul 84
Nov 84 Jan 85 May 85 Oct 65 Jan 86 Oct 86 Jan 67
79
NA
Normal GPT
GPT
GPT
Normal GPT
Normal GOT
GOT
GPT
GPT* GPT
GPT
GPT
GPT GPT
GGT
GGT
GGT
GGT
GOT
GGT
GOT
GOT
GOT
GOT
GOT
I 1978
AP
Before
Aug 77 Aug 78
Sep 78
Mar 79
Sep 80 Feb 81 Jul 81
Oct 81
Nov 81
Dec 81 Jut 82
Aug 83 Jul 84
Oct 84 May 85 Mar 87 May 87
77
NA
Normal AP
AP
AP
AP AP AP Normal AP
Normal Normal AP
AP
AP
AP*
AP
AP Retired
GGT
GGT
GGT
GGT
GPT
K
1983
GGT
Jul 81
Jul 82
Aug 83
Jul 84
Oct 84
May 85 Oct 85 Jan 86
Normal
Normal GOT
GGT
GGT*
GGT
GGT
Normal Resigned
GPT
AP
GOT
L
1980
GPT
Before
Aug 78 Oct 79
Aug 80
Ocl 80
Feb 81 Jul 81
Jul 82
Sep 82 Oct 82
Jan 83 Mar 8) Apr 83 Aug 83 Jul 84
May 85 Jan 86 Ocl 86 Jan 87
78
GGT
NA
Normal Normal
GPT
GPT
GPT
Normal GGT
GPT
GPT
GPT*
GPT
GPT
GPT
Normal** GPT* GPT
GPT
GPT
GGT
GGT
GGT
GGT
GGT
GGT
GGT
GGT
GGT GGT
GGT
GGT
AP
GOT
GOT
GOT
GOT GOT
GOT
AP
AP AP
AP AP
M
1982
GPT
Before
Jul 82
Sep R2
Jan B3
Mar 83
Apr 83 Jul 83
Aug 83 Oct 83 Jul 84
Ocl 84 Dec 84 May 85 Dec 85
82
GGT
NA
GPT GGT
GPT GGT
GPT* GGT
GPT** GGT
GPT* GGT
GPT GGT
GGT** GPT GGT
GPT GGT
GGT Bil
GPT GGT
GPT GGT
GPT GGT
Resigned
GOT
GOT
GOT
GOT
GOT
AP GOT
GOT
Bil
GOT
AP AP
Bil
AP AP
Bil Bil
NA. Nnl available The I.FT normal range: bilirubin (Bit) < I mg/100 ml; alkaline phosphatase < AP). 25 100 IU/1, serum glutamic pyruvic transaminase |GPT( < 30 Ill/I; serum glutamic oxaloacetic transaminase I GOT) < 30 IU/1; serum gamma glutamyl iranspeptidasc (GOT) < 50 IU/1; Removal from VCM exposure; ** Returned to VCM work.
14 OLL l RATIONAL MfclMC INt ( 1991 ) VOL. 4! NO. 1
They started employment in the plant between the early 1970s and 1982. While there were reports of high VCM exposures of about 100 p.p.m. in the 1970s1*'5, VCM levels in ourplM^nMilAfce considered low, ranging from 1 to 21 p-p.iHfl'^wfefe f983. After the institution of the
various engineering control measures, the VCM exposure levels in the production area ranged from 0.6 to 2.9 p.p.m. and were less than l p.p.m. most of the time since 1983. These levels were well below the recommended ACGIH ^ threshold limit values of 5 p.p.m.6. However, the VCM exposure could be high during the washing of the slurry tank as 2 workers had complaints of nausea whilst carrying out such work (the odour threshold being 2000 to 5000 p.p.m.7). Workers employed after 1982 showed
Cno evidence of liver dysfunction suggesting that VCM exposure with regard to inducing liver dysfunction has a biological threshold. It appears that VCM-induced liver ) jJysfunction is unlikely to occur at levels below 1 p.p.m.
The strict supervision on the usage of air-line respirators
during reactor cleaning in 1983 may be an added factor. Since 1974, most of the countries having PVC manufacturing plants have lowered their threshold limit values for VCM. The United States and Sweden had lowered their threshold limits (8 hours time weighted
average for VCM to 1 p.p.m.)8. Raynaud's phenomena, acro-osteolysis and sclero-
dematous skin changes had been associated with past heavy exposures to VCM1-7-9. It is not surprising that these were not detected in our workers as the general
VCM levels in our plant are low. Aryanpur8 and Lilis ei al.3 found the liver changes
(hepatomegaly, tenderness on palpation, abnormal LFT results) to be reversible after cessation of exposure. The liver progressed to what was stated to be `chronic hepatitis' when toxic exposure continued. Clinically, the liver was not palpable in all our cases although the liver scan showed hepato/ splenomegaly of varying degrees in 10 of our workers.
It is reported that the ability of the traditional biochemical tests to predict the presence of underlying histological hepatocellular damage is at best 80-85 per cent accurate10. The most effective test was GPT followed by GGT. Other studies showed that GGT was the most useful test in detecting abnormality and reflecting the extent of liver damage11 12.
On reviewiQgtfxjgial LFT results of our workers, we noted an elggSuplIlPT to be the most common initial finding with CKWbeing the second most frequently raised parameter.
In 9 of our cases, the liver dysfunction progressed rapidly upon developing the first abnormality. (The rise in LFT results were 1-2 times normal as compared to many more times in cases of infective hepatitis.) It took from 6 months to 4 years for the second parameter to become abnormal if the affected workers were not removed from further VCM exposure.
Of our workers 83.3 per cent had improvements (10 out of 12) in their LFT results within 6 months to 2 years after removal from further VCM exposure. For the 3 workers who had only one LFT abnormality initially, their LFT returned to normal on cessation of exposure, Of the 8 workers who returned to VCM work, their LFT results became abnormal again within 3 months to a year. These observations suggest that if progression of liver dysfunction is to be avoided, a worker should be removed from further VCM exposure upon developing an
A
abnormality. The elevated LFT results would then improve, indicating reversibility of dysfunction, at least in the early stages.
In our 12 workers, the latent period for the development of liver dysfunction (from first exposure to date of first abnormal LFT result) ranged from 1 to 13 years (possible cases: range = l to 13 years: median = 2.5 years: probable cases: range = 4 to 7 years: median = 6.0 years). This latent period is much shorter than that reported for the development of angiosarcoma, which takes at least 10 years7,13 t*. Thus, for the present, it is not known whether our workers will suffer from angiosarcoma of the liver at a later time. The full magnitude of this site-specific cancer risk among our workers will only be determined following full lifetime observation. One worker (H) has died of a cerebrovascular accident after a fall at home.
The chronic manifestations of VCM injury to the liver were well illustrated by the sinusoidal dilatation with sinusoidal cell activation, subcapular fibrosis, peliosis hepatitis, cirrhosis and finally angiosarcoma12. The liver biopsies of our 9 workers were reported as `non-specific fatty changes' of varying degrees although 2 were teetotallers. 3 were ex-drinkers, and the rest were social drinkers. Whether these were a misdiagnosis or the precursor stage of angiosarcoma is yet to be determined, as these features may be found in a variety of clinical conditions such as obesity, diabetes mellitus, non-A, non-B hepatitis and vinyl chloride toxicity1516.
Conclusion Exposure to VCM in industrial settings can produce hepatic fibrosis with angiosarcoma of the liver as a late manifestation3-8. The early detection of such liver disease may be of great industrial and public health importance because it remains a possibility that very early liver abnormalities may be reversible or non-progressive after workers are removed from further VCM exposure.
Our cases of VCM-induced liver dysfunction arc a relatively young group of workers in which little disease and few deaths would be expected to occur. All were below 35 years of age at the time of diagnosis. These data indicate the need for continual vigilance with environmental monitoring and medical surveillance.
Until specific tests for hepatic angiosarcoma or VCMinduced liver damage are available, we believe that our medical surveillance programme will aid detection of liver abnormalities in a possibly reversible or curable state (Table IV). Our programme involves early removal of workers with trial re-exposure. In addition, we also started a system whereby all workers exposed to carcinogens are followed-up on a regular basis for life and are registered with the local Cancer and Death Registries who will notify us upon their deaths or if they develop cancer. This may later provide useful information on the cancer risk among our exposed workers.
Acknowledgements We are grateful to the Permanent Secretary (Labour) for permission to quote from departmental records and Mrs Marsita Zain for typing the manuscript.
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16 OCCUPATIONAL MEDICINE I 1991 ) VOL. 41/NO. 1
Table IV. Medical surveillance of vinyl chloride monomer (VCM) exposed workers
Workers with any VCM exposure
i ----------------------------------------------------------- --------------- Annually
i
GOT, GPT. Bil, AP. GGT
Normal
1
One or more abnormal results
4
------L~ 1
i
Repeat the abnormal testis) in 1 month after advising worker to abstain from alcohol
i Still abnormal
1
Interview and physical examination
HBsAg, Ultrasound of liver and spleen
Normal HBsAg Normal ultrasound result
1
Temporary suspension * 3/12
i
-Repeat LFT
l
Still abnormal
i Temporary suspension x 3/12
1
Repeat HBsAg
i
HBsAg +ve
i
Temporary suspension x 3/12
i Repeat HBsAg
1
HBsAg still +ve
1
____ Permanent suspension -i
1
To follow up with 3 monthly LFT
1
Progressive deterioration
i Consider CT scan, liver angiography
i biopsy*
- -
Abnormal liver scan
Consent for a biopsy should be obtained from the worker. Suspension, removal from further VCM exposure. LFT. liver function test; GOT. serum glutamic oxaloacetic transaminase; GPT, serum glutamic pyruvic transaminase; Bil. bilirubin; AP, alkaline phosphatase; GGT, serum gamma glutamyl transpeptidase; HBsAg, hepatitis B antigen.
REFERENCES
1. Creech. JL. Jr. Johnson MN. Angiosarcoma of the liver in the manufacture of polyvinyl chloride. J Occup Med 1974; 16: 150.
2. M'akk L, Creech JL, Whelan JG, Johnson MN. Liver damage and angiosarcoma in vinyl chloride workers. A systematic detection program. J Am Med Assoc 1974; 230: 64.
3. Lilts R, Anderson H, Nicholson WJ. Daum S. Fischbein AS, Selikoff IJ. Prevalence of disease among vinyl chloride and polyvinyl chloride workers. Ann N YAcad Sci 1975; 246: 22.
4. Heldaas SS. Langard SL, Anderson A. Incidence of cancer among vinyl chloride and polyvinyl chloride workers. Br J Indus: Med 1984; 41: 25.
5. Sugita M, Masuda Y, Tsuchiya K. Early detection and signs of hepatoangiosarcoma among vinyl chloride workers. Am J Indust Med 1986; 10: 411.
6. American Conference of Governmental Industrial Hygienists. Threshold Limit Values and biological exposure indices for 1986-1987, Cincinnati, USA: 39.
7. Parmeggiani L. Encyclopaedia of Occupational Health and Safety. 3rd (Revised) edn. Geneva: International Labour Office, 1983; 2256-7.
8. Aryanpur J. Vinyl chloride: Its impact on occupational medicine
practice in Iran. J Occup Med 1977; 19: 689. 9. Nicholson WJ, Henneberger PIC, Seidman H. Occupational
hazards in the VC-PVC industry. Prog Clin Biol Res 1984; 141: 155. 10. Tambuno CH, Greenberg R. Effectiveness of federally required medical laboratory screening in the detection of clinical liver injury. Environ Health Perspect 1981; 41: 117. 11. Creech JL. Jr, M'akk L. Liver disease among polyvinyl chloride production workers. Ann S Y Acad Sci 1975; 246: 88. 12. Tamburro CH. M'akk L. Popper H. Early hepatic histologic alterations among chemical (vinyl monomer) workers. Hepatology
1984;4:413-418. 13. Spinas R, Kaminski R. Angiosarcoma of the liver in vinyl
chloride/polyvinyl chloride workers. An update of the NIOSH Register. J Occup Med 1978; 20: 427. 14. Forman D. Bennett B, Stafford J, Doll R. Exposure to vinyl chloride and angiosarcoma of the liver; a report of the register of cases. Br J Indust Med 1985; 42: 750. 15. Braunwaid E. Isselbacher KJ. Petersdorf R G, Wilson J D. Martin
JB, Fauci AS. Harrison's principles of internal medicine. 11th edn. New York: McGraw-Hill. Book Company. 1987; 1353-4. 16. WagonerJK. Toxicity of Vinyl Chloride and Poly(vinylchloride): A critical review. Environ HUh Perspectives 1983; 52: 61-6.
Requests for reprints should be addressed to: Dr S. F. Ho, Senior Medical Officer, Department or Industrial Health, Ministry of Labour. 3-7 Halifax, Singapore 0922.
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American Journal of Industrial Medicine 17:155-161 (1990)
Mortality From Liver Disease Among Italian Vinyl Chloride Monomer/Polyvinyl Chloride Manufacturers
R. Pirastu. msc. P. Comba. osc. A. Reggiani. md, V. Foa. md. A. Masina. md. and C. Maltoni, mo
The possible association in humans between nonangiosurcoma primary liver tumors l PLC-non-A). particularly hepatocellular carcinoma (HCC). and exposure to vinyl chlo ride monomer tVC'M) is supported hv both experimental anil human data. This article presents a review of the inlormation regarding 253 deaths that >ceurred in seven plants manufacturing VCM/PVC and one plant extruding PVC. The retrieval ol' clinical and pathological data, in addition to the inlormation from death certificate, is referred to as "best evidence" (BB). Bt has been earned out for 63 deaths. A total of 14 primary liver cancer (PLC) were detected: seven were angiosarcoma (PLC-A). and two of the re maining seven were hepatocellular carcinoma (HCC). In our series of 14 PLC cases, there was no significant difference between PLC-A and PLC-non-A as to length of exposure and latency. There was no noticeable difference in terms of job title between ASL and non-ASl. cases. The list of longest held jobs shows the presence of various job titles, different from auliKlave cleaner, for primary liver cancer. PLC-A and PLCnon-A. In conclusion, our observations show that VCM may have a broader carcino genicity action on the liver and that exposure lower than that occurring in autoclave cleaning can cause primary liver cancer, both angiosarcoma and nonangiosarcoma.
Key words: primary liver cancer, VCM/PVC. occupational exposure, angiosarcoma liver (ASL)
INTRODUCTION
Vinvl chloride monomer (VCM) has been shown to be a multipotential carcin ogen in rodents, i.o.. capable of causing a variety of tumors, among which angiosar coma of the liver (ASL) | Viola ct yl.. 1971; Popper ct aL. 1977; I ARC, 1987; Maltoni ct ul.. 1984; Doll. 1988: Maltoni and Cotli. !988|.
In humans, a causal relationship has been found between occupational exposure to VCM and ASL. In exposed workers, the association between the chemical and other malignant tumors--namely, brain neoplasms, lung carcinomas, and malignant
University of Rome. "La Sapien/a" Department of Animal and Human Biology fR.P.). and IstitiKo Superiors- di Sanity iP.t\. A K I. Koine. Italy Institute ol' Occupational Health "l.. Desoto." University of Milan (V.F. I. Milan. Italy Institute of Oncology F. Addarii Bologna. Bologna. Italy (A M.. C M.) Address reprint requests to Dr. Comba. Istiluto Supertore di Sanita'. Vialc Regina Blcna 299, 00161 Rome. Italy. Accepted for publication August 4. |qxu
S' 1990 Wiley-Liss. Inc.
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156 Pirastu el al.
primary liver cancer (PLC) other than angiosarcoma--has been pointed out by some investigations, but it is still debated |IARC, 1987).
The possible association in humans between nonangiosarcoma liver tumors (PLC-non-A), particularly hepatocellular carcinoma (HOC), and exposure to VCM is supported by three orders of data, dealing with: I) the experimental results of long term carcinogenicity bioassays in rats JMaltoni ct a!., I9K4|; 2) the analogies between VCM and Thorotrast carcinogenesis (Popper ei al., I977|; and 3) the observation of cases of HCC among workers exposed to VCM (Gokel cl al.. 1976; Koischwitz et al., 1981; Evans et al., 1983; Dietz et al., I9K5|.
In an experimental study, pregnant female rats were exposed by inhalation to 2,500 ppm VCM for 76 weeks (group I). Concurrently, one group of male and female offspring was exposed in the same way for 76 weeks (group II) and another for 15 weeks (group 111). Adequate control groups of breeders (group IV) and offspring (group V) were available. The incidence of ASL and HCC in the five groups was. respectively, as follows: 50.9% and 9.4% in group I; 65.1'tf and 56.5% in group II; 44.4% and 72.6% in group 111, 0 and 0 in group IV; 0 and 0.3% in group V. No sharp differences were found in the incidence of these two neoplasms between male and female offspring IMaltoni et a!., I984|.
Both VCM and Thorotrast have been shown to induce ASL and HCC in ex perimental rodents and ASL in humans; moreover, Thorotrast exposure has been documented in a variety of liver neoplasms other than ASL in humans (Kcplinger et al., 1975; Malloni and Lefeminc, 1975; Malioni, 1977; Multoni et al., 1984; Com mission of the European Communities. 1984; Multoni and Cotti. 1988}. In a com prehensive epidemiological investigation on 5,(XX) Thorotrast-injected patients and on 5,000 controls, a total of 152 PLC occurred among the exposed, whereas no cases were detected in controls. These neoplasms included both ASL and HCC [Commis sion of the European Communities, 1984).
In addition, steroids have been suggested as causative agents of both hepato cellular carcinoma and liver angiosarcoma. Women taking oral contraceptive steroids have a small increased risk for developing hepatocellular carcinoma (Klutsin, 1977], The use of androgenic anabolic steroids has been implicated in the development of hepatocellular carcinoma (Johnson ct al., I972| and angiosarcoma (Falk cl al.. 1979). In both ASL and HCC, the common accompanying precursor stage is a lesion con sisting of varying degrees of mixed hyperplasia of hepatocytes and sinusoidal cells and sinusoidal dilatation (Popper et al.. 1977|.
Few cases of HCC in workers exposed to VCM have been reported in the literature [Gokel et ul.. 1976; Koinschwitz ct al.. 1981; Evans ct al.. 1983; Dietz et al., 1985J. In the Federal Republic tit Germany, Diet/ ct al. 11985| reported three cases of HCC in VCM-exposcd workers with no history of exposure to other known liver carcinogens (such as Thorotrast and alcohol) and no signs of hepatitis B infec tion.
The present article analyzes data on the mortality from various liver diseases and provides some preliminary observations that strengthens the evidence that VCM can cause HCC in humans.
MATERIALS AND METHODS
We reviewed information regarding 253 deaths occurring in seven plants man ufacturing VCM/PVC and one plant extruding PVC. The seven plants represent all
16*0*01000
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Mortality in YCM'I'VC Manufacturers
157
TABLE I. Inscription of "Best K'tdence" Data and Aureenwnl With Death Certificate Information for Workers in Three Plants in Italy Manufacturinu VCM/1'VC
Must evidence dala
Degree of
No Ml
Clinical
Pathological
agreements
City
Plunl #
deaths
Total
data
data
DC/BE
k.ivcnna Kosignann Perrare
l 3
17 III
11 X 5f, 45
m X 45
7 80** (XOO) 3 100* IX/X) 25 71* (32/451
Italian production facilities. with (he exception of two industries in Sardinia, where the investigation is still ongoing. The results of the study, in terms of standardized mortality ratios, have been published for three cohorts [Belli ct al., 1987] and is ongoing in the remaining six plants.
Causes of death, noted on death certificates and from hospital records (when available), age at death, duration of exposure, latency, and occupational history are reported for each death.
Retrieval of clinical and pathological data, in addition to information from the death certificate, is referred to as "best evidence" (BE). BE was compiled for deaths that occurred in three of the seven plants. The type of additional data and its fre quency arc given in Table I.
"Liver disease" eases comprised 39 of 253 deaths. Deaths from liver disease were defined on the basis of cither death certificate (coded according to the Interna tional Classification of Disease. ICD) or BE-iCD (i.e., 1CD after considering the BE), when available. Two categories were identified'.
1. Primary liver cancer: ICD or BE-ICD = 155.0. which includes ASL and non-ASL cases (VIII and IX ICD Revision;.
2. Liver cirrhosis and other chronic liver disease. ICD or BE-ICD 570 = acute and subacute necrosis of the liver: 571.5 = cirrhosis of the liver without mention of alcohol; 571.9 = unspecified chronic liver disease without mention of alcohol; 573.0 = chronic passive congestion of (he liver (VIII and IX ICD Revision).
The seven ascertained Italian cases of ASL in VCM PVC manufacturers have been reported previously in the literature |Malioni, 1974; Maltoni and Rondinclla, 1980; Chiappino ct al., 1982; Maltoni et al.. 19X4; Brugnami cl al.. 1988; Chiozzini ct al., 1988]. and six arc included in (he Register of ASL cases maintained by the Imperial Chemical Industries. Two eases occurred in PVC extruders, four in poly merization workers, one in a monomer worker. All seven eases arc included in the present contribution.
RESULTS
Table II describes the 39 liver-disease deaths in terms of cause of death (ICD and BE-ICD), age at death, duration of exposure. latcncx. and longest held |ol>. 1 lie letter A labels histologically confirmed angiosarcoma eases.
We detected a total of 14 primary liver cancers (PLC): seven were angiosarcoma (PLC-A). two ol the remaining seven were HCC; for five subjects, histological data were not available, but their clinical history was not compatible with the diagnosis of
A SB?
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TABLE II. Occupations in Deaths Due to "Liver Disease*' in the Italian V.C. Study*
Duration of Years since Case # Ageat death exposure first exposure
Prevalent job
Best ICD evidence
1 62
2 42
3 55 4 74 5 48 .6 55 7 60 k 62
y 62 IU 68
n 46 12 44 13 61 14 55 15 55 16 47 17 48
IX 68 iy 52
20 66 21 45 22 43
23 50 24 50 25 50 26 46 27 37 28 44 29 41 30 59 31 49 32 65 33 50 34 43
35 55 36 61 37 56 38 61
39 62
11 20
5 16
*>
1 3 11 28
y
23
II
21 n
29 17 11
iy iy
25 6 14 4 20 25 4
22
IK
11
11
10
y
9
^14>
1 3
y
11
PVC UwJer
571.9
20
PVC loader
199.1
155.0
5
PVC bagger
571.9
29
Control
571.5
19 Autoclave cleaner 571.9
14 Dryer area helper 571.9
4
Reactor area operator 156.0
157.9
11
Dryer area operator two
155.0
31
Maintenance
155 0
25
Dryer area helper 426.0
573.0
23 Reactor area helper 571.9
7
PVC hagger
199.0
155.0
22
Autoclave operator 2500
571.9
Autoclave cleaner
159.0
155.0 A
32
Autoclave cleaner
196.9
155.0
IK Autoclave operator 155.0
23 Autoclave cleaner 571.9
28 Autoclave operator 571.5
23
Maintenance
571.9
25
Clerk
571.9
7
Compounds
571.5
*15
Maintenance Compounds
155.0 571.5
155.0A
21
Maintenance
571.5
26
Autoclave operator 571.5
155.0 A
1T6
PVC Extruder PVC Extruder
155.0 A 155.0 A
22
Reactor area operator 155.0
155.0 A
19 Reactor area operator 571.0
26 Reactor urea helper 571.9
12 Autoclave operator 571.9
15 Monomer operator 573.0
23 Autoclave operator 571.9
9 Reactor area helper 571.9
19
PVC bagger
571.9
28 PVC bagger
155.0 A
21
PVC hagger
571.9
19 Autoclave operator 571.9
20
PVC bugger
155 0
*A= Liver angiosarcoma.
ASL. Twenty of 39 "liver disease deaths'* were coded as liver cirrhosis, and ihe remaining five were unspecified chronic liver disease without mention of aleohol (1CD 571.9) and other disorders of the liver (ICD 573.0). The characteristics of the 14 primary liver cancer cases are presented in Table 111.
Mean age at death was 48 years for angiosarcoma (PLC-A), 53 years for primary nonangiosarcoma liver cancer (PLC-non-A). and 60 for liver cirrhosis and other chronic liver diseases. Mean duration of exposure was 16 years for PLC-A, 18 years for PLC-non-A. and 12 years for the other pathological entities. Mean latency was, respectively, 19. 20, and 20 years.
Mortality in VCM/PVC Manufacturers
159
TAB1.K III. Demographics and Job Titles Aiming Primary Liver Cancer Cases in the Mortality Study of Italian Manufacturers of VCM/PVC
l.ivcr angiosarcoma
Primary liver cancer
No. of cases Mean duration of exposure (years) Mean latencv (vears) Mean ape at first
exposure Mean ape at death Jnh lilies
Case no. 1
Case no. 2 Case no. 3
Case no. 4 Case no. 5 Case no. b
Case no. 7
7 lb
IV 2V.v
4X
Autoclave cleaner Autoclave operator
Maintenance Autoclave operator
Controller I'VC extruder PVC extruder Reactor area operator Warehouse and transport
PVC hugger
7 IS
20 33.6
53
Autoclave cleaner Keuclor urea helper
Maintenance Autoclave operator
Maintenance PVC loader Over area operator PVC bagger
PVC bagger
The list of longest held jobs in Table III shows the presence of job titles such as PVC loader, dryer operator, and maintenance worker for primary liver cancer both PLC-A and PLC-non-A.
DISCUSSION
Experimental and epidemiological data from the international literature suggest that VCM is a multipolcntial carcinogen; the analogies between Thorotrast and VCM carcinogenesis, ease reports of HCC in VCM exposed workers, and our present results strongly suggest that VCM can cause PLC-non-A, particularly HCC.
In Italy, only mortality data are available on a routine basis; for the entire country, there arc only four tumor registries presenting incidence data with the details of the histotype. As a consequence, it is not possible to carry out a proportional mortality analysis or any other measure of the expected number of PLC and HCC cases. In the present study. Ihe histotype was ascertained for 64% of primary liver cancer (PLC) eases; in the four tumor registries named above, the percentages were 8%, 12%. 23%. and 50%. Therefore, in the present investigation, the histotype of PLC was ascertained in greater detail than in any tumor registry. The percentages of hepatocellular carcinoma (of all PLC) wore 14% in this study and 2%. 8%, 14%. and 26%. respectively, in the tumor registries. There is no sound reason to establish a differential and biased histologic ascertainment for ASL and HCC.
In our study. ASL appeared to occur at younger age; mean age at death was 48 years for PLC-A cases and 53 for PLC-non-A. These results are comparable with U.S. data |Wong ct al.. I9X6| reporting 54 years and 61 years us mean age at death, respectively, for PLC-A and PLC-non-A. A report on the Register of ASL cases among VCM-cxposcd workers, notified to the Imperial Chemical Industries since
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1974, gives 53 years as the mean age at death lor the 138 ASL eases recorded worldwide l Forman ct al., 1985|. Mean age at first exposure was 29.9 for PLC-A and 33.6 for PLC-non-A. The same observation of younger age at first exposure for PLC-A was made in the last U.S. study: 27.2 and 36.6 |Wong ct al., 1986J. The lower age at death for ASL cases both in the U.S. and Italian series is in agreement with the hypothesis of an earlier occurrence of ASL in the frame of liver carcino genesis. but it may also be due to an early age at the lime of exposure.
In our series of 14 PLC eases, there was no significant difference in length of exposure and latency between PLC-A and PLC-non-A. There was no noticeable difference in terms of job title between ASL and non-ASL cases.
Vinyl chloride has been shown to induce ASL at very high exposure levels, as shown by the fact that most ASL cases worldwide occurred among autoclave clean ers. In the present study, the job title of the eases of both PLC-A and PLC-non-A show that these tumors may develop in VCM-exposed workers with jobs other than autoclave cleaner.
In conclusion, our observations indicate that VCM may have a broader carci nogenicity spectrum on the liver than known before and that exposure lower than that occurring in autoclave cleaning ean cause primary liver cancer, both angiosarcoma and nonangiosarcoma.
REFERENCES
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Brugnamt G. Ahhritti G. Morelli A. Maltoni C. Sohnus A. Pelliccioli G 119X8): Liver angiosarcoma in a vinyl chloride polymerization plant worker. Report ol the seventh Italian case. Med Lavoro 79:34-41.
Chiappino G, Bertuzzi PA. Barnni M, Masini T (19X2): Hepatic angiosarcoma Irom vinyl chloride report of a new Italian case. Med Lavoro 6:555-563.
Chiozzini G. Saggioro A. Pallini P. VaKecehi M. Magaroito GC. Scutiolin A. Nurdin M. Polacco A. OHboni E (1988): Angiosarcoma epalico da eloruro di vinile. Med Lavoro 79:24--33.
Commission of the European Communities <CECf (19X4): "The German Thorotrast .Study." Directorate General Science. Research and Development. f.UR 9304 EN.
Diet/ A, Langbcin G. Pernulter W 11985): Das Vinychlonde-indu/ierte hcpaloccllularc kar/inom Klin Woehensthr 63:325-331
Doll R (19HHI: Effects ol exposure to vinyl chloride. An assessment of the evidence. Scand J Work Environ Health 14:61-78.
Evans DMD. Jones WW. Kung ITM t!9X3i: Angiosarcoma and hepaUiccllular carcinoma m vinyl chloride workers. Histopathotogy 7:377-3xx.
Falk H. Thomas LB. Popper H. Ishak KG (1979i: Hepatic angiosarcoma associated with androgenicanabolic steroid' Lancet 2:1 I 20 -1 I 23.
Forman D. Bennei B. Stafford J. IX>II R (1985). Exposure to vinyl chloride and angiosarcoma of the liver: a report of the register of cases Hr J hid Med 42:750 -753
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IARC (1987): "Monographs on the Evaluation ol Carcinogenic Risks to Humans.'' Suppl. 7. Lyon. Johnson PL. Lerner KG. Siegal M <1972|: Association of androgenic-anabolic steroid therapy with
development ol hepatocellular carcinoma, l.ancel 2.1273 1276. Kcplincr ML. Goode JW. Gordon Dli. C.ilamlra JC (1975): intertill results ol exposure ol rats, hamsters
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(IHA
Mortality in VCM/PVC Manufacturers
161
Koischwii,' VI). I.clhuch WK. Lack tier K. Hermanum/ I) (I9XJ); Das vinylchloridindu/icrtc Leberangiosarkom und hcpato/cllularc kar/mom. FurlM.hr Rontgenstr 134:2x3-290,
Malioni C (1974): Angiosarcoma cpatico in operai esposti a cloruro di vintk in Italia. Med Lav 65:11-12. Maltuni C (1977): Vinyl chloride carcinogenicity: An experimental model for carcinogenesis studies. In
Hiatt HW, Watson Jl). Winstar JA (cds); "Origins of Human Cancer." Cold Spring Harbor. NY: Cold Spring Harbor Laboratory, pp I |y-l4ft. Maltoni C. Colli G II9XK); Carcinogenicity of vinyl chloride. Ann NY Acad Sci 534.146-159. Maltoni C- Lefeniine G (1975): Carcinogenicity bioassays ol vinyl chloride: Current resulls. Ann NY Acad Set 246.195-217. Maltoni C. Kondinclla R (I9K(I|: Angiosarcoma cpatico in lavoratort esposti a cloruni di vinile in llalia. Acta Oncol 1:35-49. Maltoni C. Cltni C. Vicint F. Masina A (19X4): Two cases of liver angiosarcoma among polyvinyl chloride extruders of an Italian factory producing PVC bags and other containers. Am J Ind Med 5:297-302. Maltoni C. Lefeniine G. Cilibcrti A. C'olti C', Carrclti D (19X4): Experimental research on vinyl chloride carcinogenesis. In: ``Archives of Research on Industrial Carcinogenesis." vol li. Princeton, NJ: Princeton Scientific Publishers. Popper H 11974): Hcpalic angiosarcoma in man and rodents following prolonged exposure to vinyl chloride Gastroenterology 67:794.
Popper H. Sclikoff IJ. Maltoni C. .Squire RA. Thomas LB (1977): Comparison of neoplastic hepatic lesions in man and experimental animals. In Hiatt HW. Watson JD, Winstar JA (cds): "Origin of
Human Cancer." Cold Spring Harbor. NY: Cold Spring Harbor Laboratory, pp 1359-1382. Viola PL. Bigotti A. Caputo A (1971): Oncogenic response of ral skin, lungs and bones to vinyl chloride-
Cancer Res 32:516-522. Wong O. Whorion MD. Ragland D. Klasscn C. Samuels D. Claxton K (1986); "An Update of An
Epidemiologic Study of Vinyl Chloride Workers 1942-1982. Oakland. CA: Environmental Health Associates. Inc.
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