Document 37e4DKw1YzGGwxJGXjQb3BzD0

'ischbem. Blum # IJ Clinical [ctunng work- ttrphtHvls naphmub. Amsterdam: twn cQpQntbr* naJ Irbtuute for Oklahoma upland uuiucal Analym jiomous response >ng stable labors1057-67. mcer research. Vol .on: International Set publ No 32.) British Journal of Industrial Medicine 1987,44:71115 Exposure to vinyl chloride monomer: report on a cohort study AGNES LAPLANCHE,' FRANCOISE CLAVEL,2 J-C CONTASSOT 2 GLAUDINE LANOUZIERE* From the Dipanement de Statistique Medicate.1 and Unite de Recherche 287INSERM.1 Institut Gustave Roussy. 94805 Villejuif, Atochem.3 69190 St Fons. and Solvay el Cie.* 39500 Tavaux. France abstract In 1980 a prospective exposed non-exposed cohort study was initiated in France by the Institut National de la Same et de la Recherche Medicale (INSERM U 287) to evaluate the associ ation 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"19 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 acrosteolysis. 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 Same 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. Materiab 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 1986 included if they had been living in France wtth 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 (1CD. 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 Control for confounding factors, such as cigarette smoking, alcohol consumption, and socioeconomic status, was performed using the Mantel-Haenszcl procedure.21 711 fI 712 Table 1 Distribution ofsublets by plant ,\o ofsubjects < % 1 Tavaux tSolvey) Siinl-Fons < Atochem) Roussillon (Rhone-Poulenc) AubervtfUerx (Rhone-Poulenc) Lavers (Atochem) Saint-Auban (Atochem) Bully-les-Mines (CDF Chtmte) Ribccoun (Rhone-Poulenc) Port-de-Bouc I Atochem| Commentry (AEC Rhone-Poulenc) Montluel (Atochem) Antony (Rhone-Poulenc) Total 886(40) 656(JO) 170(8) 124(6) 110(5) 84(4) 70(3) 30(1) 12(1) 18(1) 18(1) 12(1) 2200 Results From June 1980 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. Laplanche. CloveI, Contassot. Lanouztere Employees whose occupational activity was coded as worker for 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 ofexposure 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 of subjects lost to follow up Table 2 Initial characteristics ofexposed and control groups Exposed in - 1100) Age (mean + SD. yean) Foreigners Urban residence* Smoking habits: Non-smokers Smokers Ex-smokers Duration since stopping smoking (mean + SD, yean) Daily consumption (mean s SD): Cigarettes Pipes Cigars Duration smoking (mean i SD. yean): Cigarettes Pipes Cigars Inhalation Drinking habits: Non dnnkent Weekly consumption (menu SD){ Clinical signs of alcoholism Socioeconomic status. Blue collar workers! 47 4 14% 46% 27% 42% 31% *7 16 + 8 5+5 4+4 23 8 16+ 10 88 62% 13% 32 23 15% 75% *City of 15 000 inhabitants or more. tSubjects not drinking wine. beer, fortified wines, or hard bquon. {Sum of finmet of wine. beer, fortified wince, nnd herd bquon. (Worsen for mote than 75% of thetr enure work history. Controls (n - 1100) 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 >1. Lanouc'lere was coded as entire work prkers; the workers. 5en the two I" the exposed havtng been .he following tlymensation ompoundage SD) total ars (8) and re and interxposure havh. there were . level during yees. Table 3 ;ts according e duration at ;xposure and lar By 1985. 1 retired. 2% 4% were on to follow up NS NS NS NS NS NS NS NS NS NS NS NS 1 Vinyl chloride monomer, cohort study Table 3 Distribution ofexposed subjects according to levels ofexposure to VCS4 '13 Level* Duration of exposure* % mean * SD < \eorsi Tune between 1st exposure and interview mean ~ rur< 1 2 3 1 +2 1 +3 2+3 1+2 + 3 37 D - Dl - II 7 13 D - D2 - 9 - 8 8 D - D3 - 0 r 7 14 D - 16 * 7 Dl * 8 + 5 D2 - 8 - 6 10 D - 18 * S Dl - 10 * 7 D3 8 - 6 3 D - 20 - 9 D2 - II - 7 D3 . 9 * 6 16 D - 21 -4 Dl - 7 - 3 D2 7 - 4 D3 6 + 5 u*s 17 t 7 18-8 16-6 22 : 7 24-7 22 5 * I - Low; I * moderate. 3 high. tD - Total exposure duration; Dl < level t 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 (18%) exposed and 17 (16%) 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 Dunng the five year follow up period. 18 (1-6%) and 15 (14%) 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 takes 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 time 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 phystcian's personal acquaintance with the employees under his care. In this type of occupational study the Table 4 Distribution ofsubjects according tofollow up status Lost to fothn up Resigned or transferred On sick leave Exposed (1100) Control* (1100) 1P 24|2%) 3914*/.) NS 27(3%) 25(2%) NS 44(4%) 33(3%) NS Reared I55iU%> 16305%) NS 714 Laplanche. Clavel. Contassot. Lanouziere Table 5 Causes ofdeath observed during five year folio* up period* Exposed f / MU. Commix > / MO > AN causes' Cancer Circulators system Cirrhosis Trauma Others :o 9 5 0 3 17 li 3 \ 0 *No differences were statistically sigmncdnl 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."1711 1411 This study, how ever, as well as other epidemiological studies com paring exposed and non-exposed workers,4 5 * 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 lymphohaematopoieuc system, the buc cal cavity, and the skin (malignant melanoma). Our results are 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 yearfollow up period* tlCD: No 140-209) Exposed (1100) Controls f1100/ All cancers: Lun* Digestive organs Skin Buccal cavity-pharynx Anposareoma of liver Pancreas Lymphohaematopoieuc one Kidney Unknown 18 6 s 1 1 1 0 1 1 1 1 No difference* were sutuucally sifnfiicant. 15 I 6 1 j 0 1 0 0 0 Table 7 Percentage! of circulators and non-ncoplasiic respiratory diseases observed during five sear lollo* up period Rebpirjiorv system i4b<)-Mdi Circulatory svstem f 3W-45^) Hypertension Coronary insufficiency 1410-414) Cerebral vascular disease (430-4381 Arteriosclerosis ol ltmb$ (4416. 4479. 4402) Ravnauds disease (4430) Other circulatory disorders Expon-d non Pb 10". 4. * tA * i". I". 2". <. ttn'rms 1 i'Mi '"a 3. r" o 0"o 0% _s p NS mi: NS NS ns NS f) (HP NS recorded; angiosarcoma of the liver (one exposed I. skin (one exposed, one control, both epitheliomas), buccal cavity (one exposed, three controls). lymphohaematopoietic system (one exposed), and lung (six exposed, two controls). Although the number of eases 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.14*11 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 1; 1' Although suggested by some authors.3 we found no association between exposure to VCM and respi ratory disease. We are indebted to: Drs Berrod and Aubrun. RhonePoulenc. 92408 Courbcvoie. Dr Pierre; Solvay. .W'tM) Tavaux. Dr Rety: Atochem, 69190 St Fons, Drs Ouelin and Richard: Rhone-Poulenc Petrochimie. 'X i ?<) Roussillon. Drs Bourrichon. Rambaud. and Bcllcc Rhone-Poulenc Centre de Rechcrchcs. uttux Aubervilliers. Drs Colonne. Cesun. and Bcnnceh Atochem. 13117 Lavera. Drs Rutv and Lemoinc Atochem. 04600 St Auban, Dr Levcquc U)h Chimie-Usmes du Nord. 62160 Bully-les-Mines, Dr Baylac: Rhone-Poulenc Specialites chimiques, niI'o Ribecourt. Dr Lussato: Atochem, 13110 Port-de* Bouc. Dr Barrat; Rhone-Poulenc. 03600 Commentrv Drs Pirot and Favre: Alochem-Balan, (HIM Montluel. Dr Puech: Atochem. 38190 Brignoud. and Dr Lazard for their contributions of data Lanouziere r.>/< ss NS NS 0 007 NS ie exposed), itheliomas). Is), lympho id lung (six iber of cases the exposed nee was not .cases of the the exposed tis result is erence was ' Raynaud's I differences jnsid* r as for n between vpertension id.4i * 14 we found 1 and respi- un: RhoneIvay. 39500 i. Drs Quemie. 38150 ind Bcllec: is. 93308 : Bennech: Lemoine: 4uc: CDF Mines. Dr ques. 60170 10 Port-deommentry. an. 01120 gnoud. and 1 f'inv/ chloride monomer, cohort study Requests for reprints to: Dr Agnes Laplanche, Department de Statistique Medicate. Institut Gustave Roussy, Rue Camille Desmoulins. 94805 Villejuif Cedex, France. References 1 Tahcrshew (R. Gaffcy WR Mortality study of workers in the manufacture of. inyl chloride end Hi polvmers / On up Wed 1174.16 509-18, 7 Liln R. Anderson HA. Nicholson WJ. Da urn S. F Ischbein AS. Selikoff IJ Prevalence of disease among vinyl chloride and pol> wnyl chloride workers inn \ t iiad St t ><>''*.146 77-41 3 Miller A. Teirstetn AS. Chuung M. Selikoff IJ Changes in pul monary function in workers exposed lo vinyl chloride and polyvinylchloride. 4im VK ii ad Set 11*T^.24647-57 4 Nicholson WJ. Cuyler Hammond E. SciJmam H Selikoff IJ Mortality experience of a cohort of vinvl chloride polwinyl chlonde workers 4mt VK 4. mf St i 1976.J46 225-30 5 Ott MG. Langner RR, Holder BB Vinyl chloride exposure w a controlled industrial environment a long-term mortality experience in 594 employees irch Environ Health 1975:30,333-9 6 Wyatt RH. Koichen JM, Hnchxtrasser DL. etui An epidemtologic study of blood screening tests and illness histones among chemical workers involved in the manufacture ot poly vinyl chloride inn \y 4i<id Sti 1475.246 60-7 7 Fox AJ. Collier PF Low mortality rates in industrial cohort stud ies due to selection for work and survival in the industry Be J PetI Sot Wed 1976.30 775-30 It Waxweiler RJ. Stringer W. Wagoner JK. Jones J Neoplastic risk among workers exposed to vinyl chlonde inn \ I iuid Sir 1976.271 40-11, 9 Brady J, Liberatore F. Harper P. el ill Angiosarcoma of the liver: an epidemiologic survey, JSCI 1977:59-1363-5. 10 Chiazze L. Nichols WE. Wong D Mortality among employees of PVC fabricators J Ott up Wed 1977.19 623-6 11 Fox AJ. Collier PF Mortality experience of workers exposed to vinyl chlonde monomer in the manufacture of polyvinyl vhlonde in Great Bntam Be J (nd Wed 1977.34 I-10 12 Waxweiler RJ. Falk H. Mc.Michae! A. Mallov JS. Scott Grivas A. Stringer WT 1 cross-iectional epidemiological turret ot tm\l Chloride norkert. Cincinnati Department of Health. Edu cation. and Welfare, 1977 iNIOSH publ No 77-r' i 13 Anderson HA. Snyder J. Lewmson T. Wood C. Ltlis R, Selikoff IJ Levels of CEA among vinyl chlonde and polyvinyl chlonde exposed workers. Comer 1978,411560-7 14 Equitable Environmental Health. Inc Epidemiological tiud\ .9 ion/ chloride norkerr (Final report submitted to Manu facturing Chemists Association ) Washington. EEH. 19~R 15 Pierre C. Tasstgnon Jp Etude de la mortaliiechezdesiravailleurs exposes au chlorure de vtnyle. irchiees des Woludits Profttsionntlles de Wedecme du TtaeaU tt de Secunte Sotiale 1979:40 1131-45. 16 Thenaull G. Allard P Cancer mortality of a group of Canadian workers exposed to vinyl chlonde monomer J On up Wed 1981,23 671-6. 17 Forman D. Bennett B. Stafford J. Doll R. Exposure to vinyl chlonde and angiosarcoma of the liver, a report of register ot cases fir J Ind Med 1985.42:750-3. 18 Gretser E. Reinl W. Weber H. Vmylchlond-cxpovition und mor taliiat Deuischcr chcmiearbettcr im verglcich zur mortalitat nichtexpontcrter chemtearbettcr und PVC-verarbeiter Prophvlose und Erfanomie 1982:32:44-62. 19 Storetvedt Heldaaa S. Langard SL, Andersen A Incidence of can cer among vinyl chlonde and polyvinyl chlonde workers Br J /nd Med 1984:41:25-30. 20 Wartelle M. tCramar A. Jan P. rial PIGAS an interactive statis tical data base management system. In: Proceeding ot the tec end international workshop on statistical database management Los Altos: Laurence Berkely Laboratory, Statistics Canada. 1983 124-32. II Mantel N. Chi-square tests with one degree of freedom extension of the Mantel-Haenszel procedure. Journal of the imeruan Statistical Association 1963.51 690-700 ASI 0000X1696 British Journal of Industrial Medicine 1987:44:716-720 Correspondence Secondly, Soutar postulates that there is Mn ele ment of restrictive lung defect in coalminers" since, in the dust exposed groups, both the FEV, and FVC are Update oo tug disease in coal miners reduced. Contrary to what he states, obstruction is often associated with a decrease in both the FEV, and SIR--fn his editorial (1987;44:145-8) Soutar fortifies some of his arguments by quoting two papers that describe certain investigations carried out by my col leagues and me when I was associated with the Na tional Institute of Occupational Safety and Health. In doing so. he either quotes out of context or misin terprets several of our findings. Firstly, in his remarks concerning coalworkers' pneumoconiosis, he states that "irregular opacities are related to dust exposure ... and to an impairment of lung function." He supports this comment by quot ing, among other references, a paper by Amandus et al.x In reality, Amandus and his coworkers found that the two main factors associated with the presence of irregular opacities in coalminers were cigarette smoking and increasing age. A surrogate measure of exposure to dust--namely, years worked underground--was also associated to a far lesser de gree. Moreover, in non-smoking coal miners irregular opacities were not associated with impaired lung function. In virtually every investigation of the fre quency and presence of irregular opacities, whether in coalminers or other dust exposed populations, there has been an association between prevalence of irregu lar opacities and cigarette smoking. It is abundantly apparent that irregular opacities are found in many occupations other than coalmining, including work ers exposed to kaolin,1 man made mineral fibres,3 and silica.* In addition, they have been noted to occur in non-dust exposed groups including women and here again, cigarette smoking played a pre-eminent part.3 * Certainly, one cannot attribute the presence of irregu lar opacities in non-smoking granite shed or man made mineral fibre workers to emphysema and fibrosis. No one has yet suggested that exposure to silica in the absence of conglomerate silicosis leads to emphysema.7 Surely coalminers are susceptible to the same influences and agents that lead to the presence of irregular opacities in other dust and non-dust ex posed workers. The power and validity of the associ FVC. but by contrast, the residual volume iRV) is always increased and the total lung capacity iTLC) is often increased.9 10 In true restrictive impairment, all lung volumes are decreased. An increased RV is an early sign of obstructive impairment and the increase occurs at the expense of the FVC *' `1 Later, the T LC also increases but to a lesser extent: when it does so it partially and temporarily masks the effects of the in crease in the RV. In the absence of a knowledge of all lung volumes the mere presence of a reduction in the FEV, and FVC cannot be taken as an indication that restrictive impairment is present. If Soutar rereads our paper he will note that one of the points we made was that the RV was appreciably increased m smok ers whether they had bronchitis or not.12 There was. in addition, a slight but significantly increased RV in non-smokers who had industrial bronchitis or what he terms occupational bronchitis (fig 4). Secondly. he will note that we did not suggest that the airflow lim itation occurs in the upper airways, although we be lieve that most of the obstruction is located in central airways. Indeed our exact words were "flows at low lung volumes were unchanged unless expressed either at absolute lung volumes or as a percentage of TLC. this being a reflection of an increase in RV." Finally, although he maintains that some coalminers showed severe airflow obstruction due to dust exposure, he concedes that most are smokers and yet attributes the airflow obstruction mainly to dust exposure. This statement is difficult to reconcile with the postmortem study carried out by Fernie et al at the institute in which they were unable to find evidence of pulmonary hypertension or cor pulmonale in the absence of a history of cigarette smoking or PMF.13 WltC VIHROVS Chest Diseases Unit. University Hospital. PO Box 5339. Postal Stn A, London. Ontario N6A 5A5. Canada. ation between coaldust and irregular opacities are relatively weak and multiple regression analysis be References comes less reliable when there is collinearity between such factors as age, cigarette smoking, and exposure to dust. The association between them becomes even more tenuous when the interobserver variation in re 1 Amandus HE. Lapp NL. Jacobsen G. Reger RB i irregular small opacities m radiographs of coalminer' n *u- LSA Br J Ind Mtd I976.JJ 1J-7 2 Wagner JC. Pooley FD. Gibbs A. ei al Inhalation oi .fc'iu ,i.>ne gard to the reading of irregular opacities is taken into consideration.* Although the paper quoted to indi cate the problem with wide interobserver variation originates from the United States. I have similar un-. published data from Britain. and china clay dusts: relationship between miner jl.'s' i tc-i retained in the lunp and pathological chances ' > 1986,41190-6. J Weill H. Hughes JM, Hammed YY, el at Respirator, ncj.vh r . workers exposed to man-made mineral libers tm ft.. 9. ir Da I98};IJS.104-12. ' 716 here is "an elcilimne< rs" since, in *and FVC are ibstruction is _ the FEV, and .olume (RV) is parity (TLC) is impairment, all eased RV is an ind the increase Later, the TLC hen it docs so it fleets of the in* nowledgeofall eduction in the indication that Soutar rereads points we made eased in smok* A.12 There was. ncreased RV in nchitis or what <). Secondly, he the airflow limIthough we becated in central ; "flows at low ^pressed either entage of TLC, t RV." Finally, miners showed a exposure, he A attributes the exposure. This I^Astmortem tnHmstitute in ; of pulmonary e absence of a W K C MORGAN 3B. Sismltcance of tulmiMn in the ion of chin* none -unenlofy of dust chinyes. Thorax curatory health in s. Am Ret Rxsptr 1 ) Corresponded 717 4 Thenault GP. Peien JM. Johnson WM. Pulmonary function and roentfenofraphic changes in granite dust exposure. Arch Eonmi Htalih l97.2*:23-7. J Canlli AO. KoUen LM. Fischer MJ The chest roentgenogram in smoking females. Am Re* Respu Du 1973,107 135-6 6 Weiss W. Cigarette smoking, asbestos and small irregular opac ities Am Re* Respir Du 1984.130.2S3-301. 7 Sussman NB. Townsend MC. Mazumdar S Effects of multicollineanty on inference in regression analysis of occupational respiratory epidemiologic data. Am Rev Rtspu Da 1986.1suppl):AI56. 8 Amandus HE. Pendergrass EP. Dennis JM. Morgan WK.C. Pneumoconiosis: interreader vanablity in the classification of the type of small opacities in the chest roentgenogram. Am 1 Rorot Rad Therap* Sue *dtd 1974.122.740-3. 9 Levine G. Housley E. MacLeod P. Macklem PT Gas cachange abnormalities in mild bronchitis and asymptomatic asthma. N EoplJ Mtd 1970:212:1277-80. 10 Metsner P. Hugh-Jones P Pulmonary function in bronchial asthma. Br MedJ I968;i 470-2. 11 Thurlbeck WM. Henderson JA. Fraser RG. Bates DV Chronic obstructive lung disease .Wedirine 1970:49:81-14$ 12 Hankinson JL. Reger RB. Morgan WKC. Mammal expiratory flows in coalminers. Am Re* Retpir Du 1977.1 Id: 175-80. 13 Ferine JM. Douglas AN. Lamb D. Rucklcy VA. Right ventricu lar hypertrophy in a group of coalminers. Thorax 1983J* 436-42. Or Soutar replies. Morgan takes issue with some of my necessarily brief remarks on small irregular opacities in the chest radiographs of coalminers, and the type of lung functional impairment related to exposure to coal mine dust. It is not disputed that irregular opacities in coalminers are related to age and may be related to smoking. I quoted evidence that irregular opacities are related also to a surrogate index of dust exposure (years worked underground)12 and to direct mea surements of cumulative exposures to dust.2 Despite his doubts, Morgan associates himself with the paper by Amandus et alin which the authors state "smok ing, age, and years underground were independent factors which each contributed significantly to the prevalence of irregular lesions." Inter-reader differences in the interpretation of the appearances of the chest radiographs are well recog nised,2 4 but agreement between readers may still be sufficient under some circumstances to enable the demonstration of relations between certain radiographic appearances and other variables. Amandus et al (Morgan among the authors) studied inter-reader differences in recognising irregular opacities, and rec ommended that "epidemiological studies that depend on the differentiation of these types of opacity should involve a majority opinion from several interpreters rather than relying on one reader only. In addition the rigid training of readers periodically by the same stan dards should help to keep this variation within ac ceptable limits."4 Observing these precautions Dick et al confirmed a positive relation between irregular opacities and lifetime cumulative dust exposure which is unlikely to be due to chance.2 Referring to the functional implications of irregu lar opacities. Morgan correctly states that Amandus et al showed impairment of function related to irregu lar opacities in smokers but not in non-smokers.' in addition to the other evidence 1 quoted of functional impairment related to irregular opacities.156 a new study confirms impairments of function related to ir regular opacities in coalminers.' Most (86%) of the coalminers were smokers or ex-smokers, but results from 104 non-smokers included in that study were consistent with an opacity related impairment in these men also. Secondly, (Morgan's notation), of course re strictive functional defects cannot be identified with complete confidence on the basis of spirometric mea surements alone, though some patterns of abnormal ity can be suggestive. Our epidemiological studies have shown that dust exposure is related on average to a parallel reduction of FEV, than FVC, a pattern contrasting with the effects of smoking, which is re lated to a much greater reduction of FEV, than FVC, and corresponding reduction of the FEV,/FVC ra tio.* The former pattern is also shown by the group of non-smoking miners with bronchitis (assumed to be "industrial bronchitis") described by Hankinson et al.'1 Table 1 in their paper shows that FEV,, FVC. and FEV,/FVC ratio in these men were on average 0171, 0181, and 0-3% respectively lower than m an age and height matched group of non-smoking min ers without bronchitis. By contrast, the FEV,, FVC, and FEV,/FVC ratio in a group of smoking miners with bronchitis were 0-431, 0-231, and 5 5% re spectively lower than in the non-smoking miners without bronchitis. Trying to understand these differences in conventional terms, I suggested in re lation to dust induced defects "an element of a re strictive lung defect as well as airflow obstruction." Morgan for his pan suggested on the basis of these and additional measurements "that dust induced bronchitis is pnmarily affecting the larger or upper airways, and is not associated with concomitant de struction of lung parenchyma" (page 178, 3rd para, lines 14-17), while later in the article suggesting addi tional changes in small airways.4 To resolve these differences, further character isation of the functional effects of dust exposure is needed, and this will be available shortly. This new information may enable the disabling pathological le sions eventually to be identified by helping to direct the pathologist's attention to the relevant parts of the lung. Finally Morgan refers to my mention of a small group of coalminers who showed a severe inverse re lation between dust exposure and FEV,. Our reasons 718 for attributing the decrement in FEV, to exposure to dust are explained clearly in the source paper10: and just as we are not yet clear on the functionally im portant pathological changes related to dust, we also have little basis on which to judge the relevance of Morgan's point on pulmonary hypertension or cor pulmonale. Incidentally, the study by Femie et al in cluded only eight non-smoking miners without progressive massive fibrosis,11 too small a group to provide substantial support for Morgan's argument. References 1 Amandin HE. Lapp NL. Jacobxon G. Refer RB. Significance of irregular small opacities in radiographs of coalminers in the USA. Br Jind Med 1976.33:13-7. 2 Cockcroft A. Lyons JP. Anderson N. Saunders MJA. Prevalence and relauon to underground exposure of radiological irregular opacities in south Wales coal workers with pneumoconiosis. Be J Ind Mtd 1983,40:169-72 3 Dick JA. Jacobsen M, Gauld S. Pern PO. The significance of irregular opacities in the chest radiographs of Bnush coal min ers. In: Proceedings of the Vt International Pneumoconiosis Conference. Bochum, I9SJ. Geneva: International Labour Office. 1984:283-99. 4 Amandus HE. Pendergrass EP. Dennis JM. Morgan WKC. Pneumoconiosis: inter-reader variability in the classification of the type of small opacities in the chest roentgenogram. Am J Roent Rad Therapy Sue Med 1974,121:740-3. 5 Cockcroft A, Berry G. Cotes JE. Lyons JP Shape of small opac ities and lung function in coal-workers. Thorax 1982.37.765-9. 6 Musk AW. Cotes JE. Bevan C, Campbell MJ Relationship be tween types of simple coalworkers' pneumoconiosis and lung function. A nine year follow-up study of subjects with small rounded opacities. Br J Ind Med 1981.38.313-20. 7 Collins HPR. Dick JA. Bennett JG. el al. Irregularly shaped small shadows on chest radiographs, dust exposure, and lung func tion in coalworkers' pneumoconiosis. BrJ Ind Med (in press). 8 Soutar CA. Hurley JF. Relation between dust exposure and lung function in miners and ex-miners Br J Ind Med 1986:43.307-20. 9 Hankmson L. Refer RB. Morgan WKC. Maximal expiratory (lows in coalminers. Am Ret Respir Du 1977:116:175-80. 10 Hurley JF, Soutar CA. Can exposure to coalmine dust cause a severe impairment of lung function? Br J Ind Med 1986:43:150-7. 11 Ferme JM. Douglas AN. Lamb D. Ruckiey VA. Right ventricu lar hypertrophy in a group of coalworkers. Thorax 1983:31:436-42. Incidence of cancer among rinytehioride and poly vinylchloride worker*: farther evidence for an mod* aboo with malignant melanoma sir--Recently Heldaas ti al presented the results of a cancer morbidity study in vinylchloride exposed worker* (1987;44:27fi-80). They are suggesting a re lation between exposure to VC and the incidence of malignant melanomas. This suggestion is based on visual comparison of observed/expected cases in sub groups, stratified on levels of exposure or on years from first exposure (resp tables I and 2). A statistically significant trend between duration or Correspondence level of exposure and specific cancer morbidity may be tested according to Breslow et al. This test on significant trend was applied on the observed expected cases of melanoma in relation to level of exposure (table I) or in relation to years from first exposure (table 2). The probability, that the dis tribution of observed, expected cases of melanoma in the subgroups of table I and 2 was due to chance, was respectively 65% and 22%. The only significant finding is the increase in the number of cases of melanoma in the total group of workers. Such an increase, however, was also found in cohort studies of workers with widely differing oc cupations. Moreover, in all other cohort studies of workers exposed to vinylchloride no increase of mor tality from melanoma was found.2 Therefore, the present epidemiologic evidence does not support a causative relation between the incidence of melanoma and exposure to occupational vinylchloride. W F TEN SERGE DSM. Central Departmentfor Safety and Environmental Matters. PO Box 603. 6160 MH Geleen. The Netherlands. References 1 Breslow NE. Lubtn JH. Marck P. Langhoiz B Multiplicative models and cohort analyst*. Journal of the American Sioutucat 4tfOtwfioit 1983;78:1-12. 2 Nicholson WJ. Henneberger PIC, Seiderman H Occupational hazards tn the VC-PVC industry prof (7i* Biol Res 1984,141 155-75, Drs Heldaas, Laug&rd and Andersen reply: Ten Berge seems to put a great deal of emphasis on the statistical inference of the results in our study.1 We are less concerned about the statistics: in our view the emphasis should be put more on the design of ihe study. We think that the quality of epidemiological studies in occupational medicine should be judged primarily by the characterisation of the level and du ration of exposure to the potentially harmful agent, and to what extent selection has been avoided, and whether confounding has been dealt with in a proper way. Occupational diseases with presumed long latency periods have also to be dealt with in a manner which takes care of this phenomenon. A small sample size is a common weakness in the design phase of small studies. Ten Berge. however, seems to interpret this problem of small sample size and failure to obtain "statistical significance" as being evidence for non-causality. It is not obvious from ten Bcrge's letter how he has tested statistical significance rrespondence rmnooirbidity mThis lest an the t relation to o years from that the disnelanoma in chance, was Tease in the tal group of s also found differing ocrt studies of ease of morerefore, the t support a if melanoma :de. F TEN BEKCE tmental Multiplicative 'tern Siausncal *putional ml Ret ly: mphasis on our study.1 in our view iesign of the emiological . be judged vel and dumful agent, -oided, and in a proper timed long n a manner tness in the e, however, sample size x" as being us from ten jgnificance. 1 Correspondence He has. however, avoided discussing the six cases of melanoma versus one expected, which we consider to be the most important result. As pointed out in the previous study2 studies of cancer incidence have ad vantages compared with studies of mortality, particu larly for tumour sites that are successfully cured. We feel confident that the methodological aspects have been properly considered in our study.1 Con sequently, we are less concerned as to whether the results are "statistically significant" or not. We con sider the fact that two cases of melanoma developed in the a prion high risk group selected from the same VCM exposed population before the performance of the previous study2 as being of more significance for the interpretation of possible causality than the pres ence of statistical significance. Development of new cases in a preselected risk group may be of greater significance in a causality discussion than is the pres ence of "statistically significant" results. As opposed to "statistical significance," a previously selected a priori high risk group cannot be manipulated. A recent study from Du Pont. USA.1 seems to sup port our finding, but apparently our results have not attracted the author's attention.11 The current lack of adequate animal and in vitro models for studying the development of malignant melanomas makes the study of the possible causal re lation between VCM exposure and this tumour com plicated. Even so, Maltoni et al succeeded in producing malignant melanomas of the skin in Syrian golden hamsters exposed to a wide range of VCM levels.4 and they concluded that the tumours were re lated to the exposure. References 1 Hckjaai SS. Andersen A. Langird S. Incidence of cancer among vinyl chloride and polyvinyl chloride workers, a further evi dence for an usociauon with malignant melanoma. Br J Bid Med 1987:44178-80. 2 Heldaas SS. Langird S. Andenen A. Incidence of cancer among vinyl chloride and polyvinyl chloride workers. Br J But Med 1984.41.25-30. 3 O Berg MT. Burke CA. Chen JL. Walralh J. Pell S. Gallie CR. Cancer incidence and mortality in the Du Pont Company: an update. J Occup Med 1987,29 245-51 4 Maltoni C. Lefemme G. Ctliberu A. Cotli G. Carretu D. Carcinogenicity bioauays of vinyl chloride monomer a model of risk assewmem on an experimental basis, burton Health Perspeei l98l.4l.J-29. Pulmonary fibrosis w asbestos l--BlatioB worker* with tang cancer sir--Rudd's letter (1987;44:428-9) points to several interesting questions. (1) Histopathological pulmonary findings in asbes tos insulation workers with long exposure to the dust. (reviewed lung parenchyma sections submitted to me 719 by pathologists in various institutions in the United States and Canada. As expected, the material was taken from various parts of the lung, often unspecified. It is widely accepted that pulmonary asbestosis is characterised microscopically by diffuse in terstitial fibrosis caused by inhaled asbestos fibres. This was sought in my examinations in available parenchyma: Rudd argues that the subpleura! areas be excluded, a rather arbitrary preference in view of the absence of data that parenchyma here differs from parenchyma elsewhere; particularly since this part of the lung often has a considerable concentration of asbestos fibres, the result of "pleural drift" of inhaled dust. Parenthetically, lung cancer after asbestos in halation is not infrequently peripheral in ongtn. (2) I reported the presence or absence of micro scopically evident diffuse interstitial fibrosis. I also re ported that in 130 of 138 one or more asbestos bodies were seen. It is commonplace that in single thin (3p) sections, asbestos bodies may be absent. Does this mean that they are not present (sometimes in large numbers) in the lung? Of course not. The likelihood of showing asbestos bodies varies directly with the amount of tissue studied. They are more readily seen in thick (30u) sections than thin, more when bulk tis sue is digested and filtered than in sections, more when exposure has been to amphiboles than chryso lite. and more when long and thick fibres were inhaled than short and thin. It is thus not enough to say that so many or so many asbestos bodies are seen: one should immediately add comment regarding how much tissue was available for examination and how they were sought. Indeed, in our study, we did not expect to find so many cases (since, occasionally, there was only a single thin section available for re view) in which at least one asbestos body was to be seen. My colleagues consider that perhaps this was related to the diligent, prolonged examination to which each slide was subjected. (3) I was rather surprised to learn from Rudd that in the United Kingdom when there are "too few" as bestos bodies in slides of asbestos workers' lungs the diffuse interstitial fibrosis is not infrequently catego rised as cryptogenic fibrosing alveolitis. There must be a great deal of this disease nowadays in the United Kingdom among asbestos workers. And many asbes tos workers with diffuse interstitial fibrosis are not eligible for disability compensation. (4) Asbestos bodies again. I am sure that Rudd is as familiar as we are with the multitude of observations that in lung tissue of asbestos workers with or without lung cancer there tend to be myriads of asbestos fibres uncoated by the iron protein material that allows them to be visible by (relatively insensitive) optical microscopy and thereby seen as asbestos bodies. Gen erally, the uncoated fibres are demonstrable only hs ASI 000011700 720 f ` electron microscopy, after appropriate special prepa ration of the tissues. It could be--indeed, it is likely-- that in the few cases in which we did not observe asbestos bodies, uncoated asbestos fibres would have been seen if we had had an opportunity to examine an adequate tissue sample by electron microscopy. It is perhaps worth noting that we have yet to study an asbestos worker's lung in which we do not find un coated asbestos fibres (in much larger numbers than in the unexposed general population). (5) Rudd comments that if our histopathological observations were to be considered evidence of asbestosis in asbestos workers with lung cancer in the United Kingdom many more would be eligible for compensation for lung cancer. Far be it for us to ad vise how and whether United Kingdom agencies should compensate asbestos workers who suffer lung cancer. We did not proffer such opinions when, until recently, lung cancer was not considered adequate reason for compensation and we will not do it now. Parenthetically, can Rudd tell us what proportion of workers with lung cancer, after important oc cupational exposure to asbestos, have been denied compensation because a board's histological/asbestos body criteria were not met? We appreciate Rudd's comments. They reflect im portant issues in the pathogenesis of lung cancer, not addressed in the bare data reported in our paper but useful as we nowadays grapple with concomitant is sues of prevention, compensation, and public health Correspondence control. Perhaps the letter reflects these. "1 do not intend to suggest that the fibrosis seen in these cases was not caused by asbestos exposure. " This acknowl edgement goes to the heart of the matter. Besides the theoretical pathogenetic connotations, which can be argued about, there are the practical questions of whether and how we might provide help for those found injured after inadequate protection in the past. Mount Sinai Medical Center. I Gustave L Lew Place. Sew York. NY 10029. USA. Y SLZL'KI H KIPEN Rl.TH LILIS I J SELJKOFF Notice The Health and Safety Executive Library and Infor mation Service has indexed all articles relevant to health and safety at work in the British Journal of Industrial Medicine from 1944 to date. Approximately 1600 items are available in the HSEL1NE database, information on which is available on Pergamon Infoline Computer Services, European Space Agency Information Retrieval Services, Datastar. Compact Disc Read Only Memory.