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in. Blum IJ- Clsnivui rine nunh- 'ffiS(erd.irn i upacti,ir. '(Utile tor fna upljnd Analysis ' response tobora- dilrch. V<*l vrnationjl No }2, t British Journal of Industrial Medicine 1987:4-4:71 1-715 Exposure to vinyl chloride monomer: report on a cohort study AGNES LAPLANCHE.1 FRAN^OISE CLAVEL.: J-C CONTASSOT.J GLAUDINE LANOUZIERE4 From the Department de Staiistique Medicate.1 and Unite de Recherche 287 INSERM.1 Institut Gustave Roussv. 94805 Villejuif. Atochemf 69190 St Fons. and Solvayet Cief 39500 Tavaux. France \bstract In 1980 a prospective exposed/non-exposed cohort study was initialed in France by the Institut National de la Sante et de ia Recherche Medicale (INSERM U 287) to evaluate the association between mortality and cancer morbidity and occupational exposure to vinyl chloride mono mer (VCM). Eleven hundred VCM exposed subjects and 1100 VCM non-exposed controls matched for age ( + 2 years), plant, and physician were included and followed up over a five year period for vital, health, and occupational status. The percentages of deaths observed among the exposed (1-8%) and non-exposed subjects (1-6%) did not differ. Eighteen (1-6%) and 15 (1-4%) cases of cancer were reported among exposed and non-exposed subjects, respectively (NS). One case of angiosarcoma of the liver occurred among the exposed group; six cases of lung cancer occurred among exposed subjects and two among non-exposed subjects (NS). The percentage of diseases of the circulatory system was higher (p < 0-02) in the exposed group than in the non-exposed group; this difference was explained mainly by the high incidence of Raynaud's disease (p < 0-006). The percentages of diseases of the respiratory system did not differ between the two groups. Several epidemiological studies of subjects occupationally exposed to vinyl chloride monomer (VCM| have been conducted.1'14 Although these studies differ in size and design, and cover different periods, they all conclude that the risk of some diseases, angiosarcoma of the liver (ASL) and aerosieolysis. for example, is increased by exposure to VCM. In 1980 a prospective exposed/non-exposed cohort study was initiated by the Institut National de la Sante et de la Recherche Medicale (INSERM U 287) in France. The main purpose of this study was to evaluate the association between mortality and mor bidity (especially from malignant tumours) and occupational exposure to VCM. Materials and methods The present study included most of the French VCM polymerisation plants. The exposed group consisted of 40-55 year old employees, either presently exposed or having been exposed to VCM. Foreigners were Accepted 13 October 1VK6 included if they had been living in France with their family for at least five years. Controls were employees never exposed to VCM. Each control was matched to one exposed subject for age (-2 years), plant, and physician. Interviews for initial data collection were conducted by each plant physician over a year. Data collected included identification, employment history (the entire work history was coded), occupational cat egory. and amount of exposure to VCM (defined for polymerisation functions as low since 1976. moderate between 1970 and 1976. and high before 1970), and medical history in addition to smoking and drinking habits. Each year until December 1985 the subjects were followed up for vital, health, and occupational status. Causes of death and specific abnormalities were coded according to the International Classification of Diseases (ICD. 9th revision). Sub jects who had terminated their employment (resigned, transferred, or retired) were followed up by each phy sician by post. The data were analysed using the PIGAS system.10 Control for confounding factors, such as cigarette smoking, alcohol consumption, and socioeconomic status, was performed using the Mantcl-Hacnszcl procedure."1 711 R&S 001658 712 Laplartche. Clavel, Conrassot. Lanouziere Table 1 Distribution ofsubjects by plant .Vo ofsubjects (%) Tavaux (Solvav) Samt-Fons (Atochcm) Roussillon {Rhonc-Poulcnc) Aubcrvilliers (Rhone-Poulenc) Lavcra (Atochcm 1 Saim-Auban (Atochcm) Bullv-les*Mmcs (CDF Chimic) Ribccourt (Rhonc-Poulcnc) Porl*de-Bouc (Atochemi Commcntrv (AEC Rhone-Poulcnc) Montlucl (Atochcm) Antony (Rhonc-Poulcnc) Total 886(40) 656(30) 170(8) 124(6) 110(5) 84(4) 70(3) 30(1) 22(1) 18(1) 18(1) 12(1) 2200 Results Irom June 19S0 to May 1981. 2200 employees were included: 1100 exposed and 1100 controls in 12 plants (table I). Two plants recorded over 70% of the entire cohort. DESCRIPTION OF THE CHARACTERISTICS OF THE COHORT Most initial characteristics, smoking, and drinking habits did not differ among exposed and non-exposed subjects (table 2). A socioeconomic characteristic was defined. Employees whose occupational activity was coded as worker lor more than 75% of their entire work history were considered as blue collar workers; the remainder were classified as white collar workers. These percentages did not differ between the two groups. DESCRIPTION OF EXPOSURE TO VCM At the time of the interview, only 36% of the exposed group was exposed to VCM. the rest having been exposed in the past. They represented the following occupations: CV synthesis (17%), polymerisation (54%), copolymerisation (7%), and compoundage and pharmacy (22%). The mean (SD) total duration of exposure to VCM was 14 years ( +8) and the mean time between the first exposure and inter view was 18 years (8). The amount of exposure hav ing been coded as low. moderate, or high, there were seven different combinations of exposure level during the entire work history of exposed employees. Table 3 shows the distribution of exposed subjects according to these combinations, the mean exposure duration at each level, and the time between the first exposure and the interview. FOLLOW UP OF THE COHORT The follow up of the two groups was similar. By 1985. 15% of the subjects initially included had retired. 2% had resigned or been transferred, and 4% were on sick leave. The percentage ol'subjeeis lost to follow up Table 2 Initial characteristics ofexposed and control groups Exposed {n HQO) Aeetmean z SD. ycursi Foreigners Urban residence" Smokina habits: Non-smokers Smokers Ex-smokers Duration since stopping smoking (mean z SD, years) Daily consumption (mean t SD): Cigarettes Pipes Cigars Duration smoking imean r SD. years): Cigarettes Pipes Cigars Inhalation Drinking habits: Non drmkcrst Weekly consumption (mean SD){ Clinical signs ot alcoholism Socioeconomic status: Blue collar workers} 47 + 4 14% 46V. 27% 42% 31% 8+7 I68 55 4+4 23 + 8 16 + 10 8+8 62% 13% 32 + 23 15% 75% "City of 15000 inhabitants or more. Subjects not dnnkinc wme. beer, fortified wines, or hard liquors. ^Sum ol glasses ot wtne, beer, fortified wines. and hard liquors. ^Workers for more than 75% of (heir entire work history. Controls (n a 11001 48+4 14% 45% 24% 46% 30% 87 16 + 9 5+6 4+4 24 + 8 18+11 9+9 64% 12% 31 + 20 11% 72% P NS NS NS NS NS NS NS NS NS NS NS NS NS NS 0 003 NS Vinyl chloride Table 3 Distni VfC 33 O) +2 o 0 --A + 3 cn 01 (a r 3 1-2 + 3 * I s* Low*. 2 * tO - Total c*P during the ti status was ui not differ be (table 4). mortality During the exposed am These percc shows the c. morbidit- During the 15 (1-4%) exposed a These perct tribution o case of ang exposed g reported, s only two a percentage two group latory svst among thcontrol gt considerec cerebrova- Tabic 4 0 Exposed (IP Controls (11 P r> La 0991-0 S * * 1 Vinyl chloride monomer, cohort study 713 Table 3 Distribution ofexposed subjects according to levels ofexposure to VC\f Level* Duration ofexposure* % mean Zi $D (years) Time between ht exposure and interview mean z. 1 years i 1 \ I +2 1 +3 : -> 3 1 - TJ 37 . D ** Dl = 11 * 7 13 D - D2 - 9 * 8 8 D = D3 - 9 + 7 14 D - 16 + 7 Dl - 8 + 5 D2 - 8 + 6 10 D - 18 + 8 Dl -- 10-1-7 D3 - 8 + 6 3 D = 20 + 9 D2 - 11 + 7 D3 = 9 + 6 16 O 21 +4 Dl - 7 + 3 D2 * 7 - 4 D3 = 6 - 5 14 + g 17 4-7 18 + 8 19 6 22 + 7 24 4- 7 22 + 5 '1 - i.ow; 2 - moderate: 3 " high. *D = Total exposure duration: Dl level I exposure duration; D2 = level 2 exposure duration: D3 * level 3 exposure duration. during the five years--that is, whose vital and health status was unknown--was 3%. These percentages did not differ between exposed and non-exposed groups (table 4). MORTALITY OF THE COHORT During the five year follow up period. 20 (1-8%) exposed and 17 (1-6%) non-exposed subjects died. These percentages did not differ significantly. Table 5 shows the causes of death. Raynaud's disease, and other vascular diseases.The only association found concerned Raynaud's disease, and other vascular diseases. The only association found concerned Raynaud's disease (p < 0 007). The percentage of diseases of the respiratory system (ICD: 460-519) did not differ between the two groups and no case of pulmonary fibrosis was recorded. These results were not materially altered by adjustment for tobacco smoking, alcohol status, and socioeconomic category. MORBIDITY OF THE COHORT During the five year follow up period, 18 (1-6%) and 15 (I4%) cases of cancer were reported among exposed and non-exposed subjects, respectively. These percentages did not differ significantly. The dis tribution of cancer sites is presented in table 6. One case of angiosarcoma of the liver occurred among the exposed group. Eight cases of lung cancer were reported, six among the exposed subjects (0-5%) and only two among the non-exposed subjects (0-2%); the percentages of lung cancer did not differ between the two groups. The percentage of diseases of the circu latory system (ICD: 390-459) was higher (p < 0 02) among the exposed group (10%) than among the control group (7%) (table 7). Six categories were considered: hypertension, coronary insufficiency, cerebrovascular disease, arteriosclerosis of the limbs. Discussion Subjects were included in the study if they were under 55 in order to allow a five year minimal follow up without too many withdrawals, as retirement usually lakes place around age 55-60. Moreover, the subjects had to be over 40 for two reasons: firstly, to include only subjects who had been exposed to VCM for a sufficiently long lime when levels of exposure were appreciably higher than at present and. secondly, because the incidence of malignant disease increases with age. Considering the percentage of retired, resigned, or transferred subjects, the percentage of subjects lost to follow up (3%) is low. This results from each physi cian's personal acquaintance with the employees under his care. In this type of occupational study the Table 4 Distribution ofsubjects according to follow up status Lost to follow up Resigned or transferred Exposed 11100) Controls (1100) P 24(2%) 39(4%) NS 27(3%l 25(2%) NS On sick leave 44(4%) 33(3%) NS Retired 155(14%) 163(15%) NS 714 Laplanehe, Clave!. Contassot, Lanouziere Table 5 Causes ofdeath observed duringfive year follow up period' Exposed (i t001 Controls i /1001 Ad causes: Cancer Circulatorv svstem Cirrhosis Trauma Other* 20 ,9 5 0 3 3 17 tl 3 * 1 0 'No differences were statistically significant. exposed group is exposed not only to VCM but also to various other agents with possible pathological effects. To control for these different exposures, the control group included workers whose exposure was similar to that of the exposed subjects, except for VCM. Exposed and non-exposed subjects were not matched by socioeconomic characteristics but the percentage of blue collar workers did not differ between the two groups; moreover an adjustment for this factor was made. The mean time between the first exposure to VCM and the interview was 18 years. This is important, because a long gap is necessary between exposure and the onset of disease, especially in the case of cancer, which may take eight to ten years to develop. Most surveys have shown a significant reduction in the mortality of VCM workers as compared with mortality in the general population; this is called the "healthy worker effect."1 711 14 15 This study, how ever, as well as other epidemiological studies com paring exposed and non-exposed workers,418 found no difference in mortality between the two groups. Most studies clearly conclude that the target organs for VCM include the liver, the brain, the lung, and probably the lymphohaemaiopoietic system, the buc cal cavity, and the skin (malignant melanoma). Our results arc not consistent with those previously reported. In our study no significant association between cancer morbidity and exposure to VCM was observed, and tumours at the following sites were Table 6 Causes ofcancer observed during five year follow up period' fICD: bio 140-209) Exposed t! 100) All cancers: Lung Digestive organs Skin Buccal cavity-pharynx; Angiosarcoma of liver Pancreas Lymphohaemaiopoietic Bone Kidnev Unknown IS 6 5 1 1 I 0 1 1 1 1 'No differences were statistically signtiicant. Controls (1100} is 6 1 3 0 1 0 0 0 T Table 7 Percentages ofcirculatory and non-neoplastic respiratory diseases observed duringfive yearfollow up period Respiratory svstem (460-519) Circulatorv svstem < J9G-459); Hypertension (401-405) Coronarv insurticiencv <410-414) Cerebral vascular disease (430-438) Arteriosclerosis of limbs (4476.4479. 4402) Ravnaud's disease t JJ30) Other circulatory disorders Exposed Controls i1100) UOOi p i'9 I0ai / 4% 3% _>r 2% 1% 0% 1% 1% 1% ov 2% NS 0 02 NS NS NS NS 0 007 NS recorded: angiosarcoma of the liver (one e t posed). skin (one exposed, one control, both epitheliomas), buccal cavity (one exposed, three controls), lymphohacmatopoietic system (one exposed), and lung (six exposed, two controls). Although the number of cases of lung cancer was three times greater in the exposed than in the non-exposed group, the difference was not significant. In our study a higher percentage of diseases of the circulatory system was observed among the exposed group compared with the controls. This result is consistent with others.14711 The difference was explained mainly by the high incidence of Raynaud's disease but also by the addition of small differences observed in most of the vascular categories consid ered, whose physiopathology may be the same as for Raynaud's disease. A possible relation between exposure to VCM and the occurrence of hypertension or coronary insufficiency has been reported.13 18 Although suggested by some authors,316 we found no association between exposure to VCM and respi ratory disease. We are indebted to; Drs Berrod and Aubrun: RhonePoulcnc, 92408 Courbevoic. Dr Pierre: Solvav, 39500 Tavaux. Dr Rety: Atochcm, 69190 St Fons. Drs Quclin and Richard: Rhone-Poulcnc Pctrochimie. 38150 Roussillon. Drs Bourrichon. Rambaud, and Bellcc: Rhonc-Poulenc Centre de Rccherchcs, 93308 Aubcrvilliers. Drs Colonnc. Cestin. and Benncch: Atochem. 13117 Lavcra. Drs Ruty and Lcmoine: Atochcm. 04600 St Auban. Dr Levequc: CDF Chimic-Usines du Nord, 62160 Bullv-les-Mincs. Dr Baylac: Rhonc-Poulenc Specialites chimiqucs. 60170 Ribccourt. Dr Lussaio: Atochcm. 13110 Port-dcBouc, Dr Barrat: Rhonc-Poulenc. 03600 Commcntry, Drs Pirot and Favrc; Alochcm-Balan. 01120 Monilucl, Dr Pucch; Atochcm. 38190 Brignoud. and Dr Lazard for their contributions of data. Vinyl Requ< Depai Gusta Refer ;t : La ; 3M 4N 5o x 33 4 ft0 in 03 O O o 1 inyl chloride monomer, cohort study Requests for reprints to: Dr Agnes Lapianche, Department de Statistique Medicate. Institut Gustave Roussv. Rue Camille Desmoulins, 94805 Villejuif Cedex. France. References I Tubershaw 1R. Guffey WR, Mortality study of workers in the manufacture of vinyl chloride and its polymers. J Occup Med 1974:16:509-18. I Lilis R, Anderson HA. Nicholson WJ. Daum S. Fischbcin AS. ScJikofT IJ. Prevalence of disease among vinyl chloride and polyvinyl chloride workers. Ann NY Acad Set 1975:246:22-41. J Miller A, Teirstcin AS, Chuang M. SelikofT li. Changes in pul monary function in workers exposed to vinyl chloride and polyvinyl chloride. .-Inn NY Acad Sa 1975:246:42-52, 4 Nicholson WJ. Cuyler Hammond E. Seidmam H,, Sclikotf IJ. Mortality cxpenence of a cohort of vinyl chloride--polyvinyl vhlondc workers. Ann NY Acad Si i !976;2461225-30. ' Oil MCi. Langncr RR. Holder BB, Vinyl chloride exposure in a controlled mduvlriul environment: a long-term mortality experience in 594 employees. Arch Environ Health 1975:30-333-9 n Wyatt RH. Kotchcn JM, Hochslrubser DL, dot. An epi demiologic study of blood screening tc*t$ and illness histones among chemical workers involved in the manufacture of poly vinyl chloride, Ann ,VK Acad Sa 1975:246.SO-7 7 Fn% AJ. Collier PF. Low mortality rjtes in industrial cohort stud ies due to selection for work and survival in the industry. Be J Prev Sot Mat 1976:30-225-30. X Waxweilcr RJ. Stringer W, Wagoner JK. Jones J. Neoplastic risk jmoni: workers exposed to vtnvl chloride. Ann NY Acad Set 1976:271.40-X, 9 firajv J. Liberatore F. Harper P. etui. Angiosarcoma of the liver: an epidemiologic survey. JNCt 1977:59:13X3-5. 10 Chia/.zc L. Nichols WE. Wong O, Mortality among employees of I1 VC fabricators. J Occup Med 1977; 19.623-8 715 11 Fox AJ. Collier PF. Mortality experience of workers exposed to vtnyl chloride monomer in the manufacture of polyvinyl chlo ride in Great Britain. Be J Ind Med 1977:34:1-10. 12 Waxweilcr RJ. Falk H. McMichael A. Mallov JS, Scott Grivas A. Stringer WT. A cross-sectional epidemiological survey of vinyl chloride workers, Cincinnati: Department of Health, Edu cation, and Welfare, 1977, (NIOSH publ No 77-177.) 13 Anderson HA, Snyder J, Lewinson T. Wood C. Litis R, Selikoff IJ. Levels of CEA among vinyl chloride and polyvinyl chlonde exposed workers. Cancer 1978;42:1560-7, 14 Equitable EnvironmcrtcaT Health, Inc. Epidemiological study of vinyl chloride workers. (Final report submitted to Manu facturing Chemists Association.) Washington: EEH. 1978. 15 Pierre C. Tassignon JP. Etude dc la mortalite chez des travailleurs exposes au chlorure dc vinyle. Archives des Maladies Professionneiles, de Medecme du Travad <t de Secunte Sociale 1979;40:1131-45. 16 Thenault G. Allard P. Cancer mortality of a group of Canadian workers exposed to vinyl chlonde monomer. J Occup Med 1981;23:671-6. 17 Forman D, Bennett 8. Stafford J. Doll R. Exposure to vinyl chlo nde and angiosarcoma of the liver: a report of register of cases. Sr J Ind Med 1985:42:750-3. 18 Grciser E, Reinl W. Weber H. Vinylchlond-exposuion und morUlitat Dcutschcr chemiearbcttcr im vergleich zur mortalitat nichtcxponicrter chemicarbciter und PVC-vcrarbeiier. Prophy* laxe und Ergonomie 1982:32:44-62. 19 Storctvedt HeldaasS, Langard SL. Andersen A. Incidence of can cer among vinyl chloride and polyvinyl chlonde workers. Br J Ind Med 1984;41:25-30. 20 Wartellc M, Kramar A, Jan P. et al. PtGAS: an interactive statis tical data base management system. In: Proceedings oj the sec ond international workshop on statistical database management. Lo$ Altos; Laurence Berkely Laboratory, Statistics Canada, 1983:124-32, 21 Mantel N. Chi-square tests with one degree of freedom: extension of the Manlcl-Haenszel procedure. Journal of the Amencun Statistical Association 1963.58:690-700. R&S 001662