Document YN1Nx6RYjV6x5Mm2qVKrjEpO

REPORT ;:c. T,-/-2/k uoc 612.2 : 67?.7^3 AN EPIDEMIOLOGICAL STL'OY OF THE LUNG FUT.'CTICM CF -CKCERG AT A FACTORY MANti f'ACT'jai I.'G POLYVINYLCHLORIDE by ME Lloyd S Gauld L Copland CA Soutap JANUARY 1982 CMft 007702 INSTITUTE 07 OCCUPATIONAL MED CINE AN EPIDEMIOLOGICAL STUDY OF THE LUNG FUNCTION OF WORKERS AT A FACTORY MANUFACTURING POLYVINYLCHLORIDE by MH Lloyd, 3 Gauld, L Copland, CA Soutar Medical Branch Institute of Occupational Medicine, Roxburgh Place, EDINBURGH EH8 9SU. (Tel. 031 667 5'>3'0 JANUAKY 19S2 CMA 007703 (ii) CONTENTS Page No. ABSTRACT ............................................................................... (iv) 1. INTRODUCTION ................................................................ 1.1 Respiratory effects of VCM and PVC . . 1.1.1 Animal studies ...... 1.1.2 Clinical studies ................................ 1.1.3 Epidemiological studies ... 1*2 The present study ....... 1.2.1 The PVC factory ................................ 1.2.2 Tne foundry ...... 1 1 2 2 3 3 4 5 2. KETEGDS ....................................................................... 2.1 Selection of the surrey papulation 2.2 The medical survey ...... 2.3 Methods of analysis ...... 2.3.1 Classification of smoking histories 2.3.2 Analysis of data from total survey population ........................................ 2.3.3 Selection of cases and controls . 2.3.4 Case-control study ..... 6 6 6 7 7 7 8 8 3. RESULTS .............................................................................. 3.1 Description of total survey population 3.2 Analysis of lung function data from total Survey population ............................................... 3.2.1 Calculation of predicted values and standardised residuals 3.2.2 Distribution of standardised residual values of T.eo and FEVt for total survey population ................................ 3.2.3 Selection of eases and controls 3*3 General features of cases, controls and the total survey population ..... 3.3*1 Age, height and weight ... 3.3.2 Employment status and smoking habit 3*3*3 Lung function ....... 10 10 10 10 10 10 11 11 11 11 CMA 007704 (ill) Page No. 3.4 Clinical description of Ttco cases and FEVj cases ......... 3.3 Case-control stud? ........ 3.5*1 Occupational histories of case3 and controls ........ 3*3*2 Smoking habits of cases and controls . . 12 12 12 14 4. DISCUSSION.......................................................................................16 5. CONCLUSIONS AND RECOMMENDATIONS........................................ ....... 19 ACKNOWLEDGEMENTS REFERENCES TABLES FIGURES APPENDICES 4 CMA 007705 Report No. TM/82/4 <iv) INSTITUTE OF OCCUPATIONAL MEDICINE AN EPIDE-'IQLCGICAL STUDY CF THE LUNG FUNCTION OF WORKERS AT A FACTORY MANUFACTURING FCLTVINYLCELCRIDE by MB Lloyd, S Gauld, L Copland, CA Soutar ABSTRACT W- have conducted an epidemiological study to investigate a report that some men working in a factory manufacturing polyvinylchloride (PVC) had abnormally low values of one lung function test, namely the single breath transfer factor for carbon monoxide (Tkco). We studied 265 present and past employees of the PVC factory, and 219 men from the workforce of a nearby foundry. The foundrymen were included to increase the number of men with little or no exposure to possible respiratory hazards at the PVC factory. Each man's Ttco wes measured, and smoking history and detailed occupational history obtained. More detailed lung function tests were carried out on the PVC workers only (forced expiratory flow-volume curves). The study consisted of two parts; measurement of the Tueo of current and past employees at the factory and current foundry employees and examination of the distribution of residuals after allowing for age, height, weight and smoking habit, to search for evidence of an excess of men with low values of Tueo; and a ease-control study. In this, men with the lowest Tkco after allowing for age, height, weight and smoking habit were selected as cases, and their occupat ional history compared with that of two groups of controls; one group selected from those with near average gas transfer values, and another group from thoae with the highest values. The Tkco results among this combined population conformed to a Normal distribution after allowing for age, height, weight and smoking habit, and did not suggest that a substantial number of men had clinically important impairment of their Tkco. The 31 men selected as 'eases' included 15 men whose Tkco was abnormally low (less than 7& of published predicted values), of whom jHnU^were PVC workers and ware foundrymen. Among the 19 cases working at the PVC factory the pattern of lung function abnormality suggested that the low Tko was 007706 (v) accompanied by evidence of airflow obstruction in 11 men, suggesting the presence of emphysema, but was an isolated functional abnormality in the other eight, possibly suggesting the presence of pulmonary fibrosis or abnormalities of lung perfusion. PVC workers wai*e slightly over-represented among the cases, although this difference could easily have arisen by chance. Men who had worked on jobs at the PVC factory which were close to the pressure vessels where exposure to vinyl chloride monomer was most likely to have occurred in the past, were also slightly over-represented among the cases, and this difference approached statistical significance at conventional levels. There was, furthermore, a statistically significant association between low Tcco and a history of having worked at the PVC factory before 1975* This date is important because it was at this time that.exposure of the workforce to vinyl chloride monomer was drastically reduced, in the light of information about some of the potential hazards of this gas. The oases included slightly more smokers than the controls, and those eases who smoked, smoked slightly more heavily than controls. The relative importance of these and other factors in causing the lung functional abnormalities is not clear, but these findings give some support to the hypothesis that work in the PVC factory before 1975 involved exposure to a substance that caused impairment of lung function in a small number of men. There was no evidence of a relationship between low TLco values and current working conditions at the PVC factory or with past or present conditions at the foundry. The results suggest that more detailed studies of the relation ships with vinyl chloride monomer, polyvinylchloride, smoking habit and other causative factors would be desirable, together with a clinical assessment of the lung damage in selected men* CMA 007707 1. INTRODUCTION The health of workers employed in the manufacture of polyvinylchloride (PVC) has teen a cause of concern during resent years. Some adverse effects of exposure to vir.yi chloride monomer (VCM) are well recognized, but lung disease in man has net been shown to be related to exposure to VCM. exposure to airborne ?VC dust, however, has been shown to cause slight impairment of lung function and slight chest radiographic abnormalities. Vitivl chloride is the basic raw material used in the production of PVC. Although the manufacturing process was first developed in 1923 in the USA it was not until JO years later that evidence of the toxic effects of vinyl chloride exposure began to accumulate. CCP-llr. (1 5) -/.'is the first to describe ecro-osteolysis in reactor cleaners in Belgium and in the following year bUCTU (19o7) described Raynaud's phenomenon among workers in a PVC factory. Changes in the skir. and internal organs were subsequently recognized and in '97L the term 'vinyl chloride disease' was used to describe the 3yrdrcme which l.as cany features in common with scleroderma (VHLTXAN al., 1975). The hepatic effects of excosure to VCM have aroused the most interest and include nen-malignant changes. It was the discovery cf. the association between vinyl chloride exposure and angiosarcoma of the liver (CBESCH and JOHNSON, 17*0 which caused the greatest concern and affirmed the need for stricter control of exposure levels. In 19"5 regulations were introduced which established a ceiling exposure value of 50 parts per milTicn (ppm) and an eight-hour time weighted average (TaA) of 10 ppm. In 1930 the permitted maximum exposure was reduced to an annual average of 5 ppm. 1.1 Respiratory effects of VCM and PVC The work described in this report was canfined to a study of the lung function of workers in a factory producing PVC where men were exposed potentially to VCM, PVC and the other compounds used in the manufacturing process. Previous studies involving the use of animals, observation on patients and epidemiological surveys, have provided information on the potential respiratory effects of these compounds. CMrt 007708 2 1.1.1 Animal studies The toxicity of both VC and PVC has been investigated in animal experiments. PHGDAN et al. (1975) exposed guinea pigs to 1C9S vinyl chloride concentration for two hours daily for periods of up to three months. At autopsy the lungs of all exposed animals showed the presence of fibrosis which was most severe in the animals which had had the longest exposure time* AGA5WAL et al. (1973) studied the effect of intratracheal injections of PVC dust In rats and found that inflammatory changes were induced in the terminal and respiratory alveoli and that granulomatous lesions associated with multinucleated giant cells developed. Similar giant cells and histiocytes were identified in the alveoli of the lungs of small mammals which were kept in the bagging area of a PVC factory (F20NGIA at al.. 197V). 1.1.2 Clinical studies There have been isolated case reports of pulmonary disease in workers employed in factori.es manufacturing PVC. ABNAOT) et al. (1973) studied a 55-year-old man who had worked for 25 years in the bagging plant of a PVC factory. Eis chest X-ray showed cncroncdular shadowing and lung biopsy revealed large numbers of macrophages containing particulate material and moderate diffuse fibrosis and a few alveolar grasulomata. However, his symptoms were few and apart from a slight reduction is. vital capacity, his lung function tests including his transfer factor for carbon monoxide wore normal. His disease was probably related to PVC dust rather than VCtt. DAEXE (1976) investigated IV men who aad been employed in a PVC manufacturing plant exposed to VCH end all of whom complained of breathlessness. He found that thoir chest radiographs were normal. In six of these men transfer factor for carbon monoxide is reported as being impaired but no measurements or details of other lung function tests are given. Lung biopsy from one of the men showed focal alveolar wall thickening and macrophages present in alveolar spaces. LANGS et al. (1973) described some cases of VC workers with impairment of transfer factor for carbon monoxide, but the relationship with occupation was not* clear. CMA 007709 1.1.3 3. Epidemiological studies Studies of pulmonary function of workers employed in PVC manufacturing plants hare produced conflicting results, and it has not always been possible to separate the effects of rVC dust from potential effects of VCM. A high prevalence of abnormal lung function, mainly obstructive in type, was found b7 MILLER e_t al. (1975) and LILIS al. (1975; 1976) among workers in two PVC manufacturing plants in the United States of America but smoking was not taken into account in the analysis. Smoking effects were allowed for in the study by GAMBLE et al. (1976) which compared the lung function of workers in a PVC plant with that of rubber workers and chemical workers exposed to VCM: no significant differences were found in the lung function of these three groups but no measured personal exposures were available. VERTKIN et al. (1970) studied 96 PVC workers in the USSR and found a high prevalence of chest radiograph abnormalities but the majority of the workers had normal lung function testa. CHIVER5 et al. (1980) aimilarly found no apparent impairment of lung function among 309 employees in a PVC factory of whom 10^ were exposed te PVC dust only, 112 to non-chlorinated solvents only and the remaining 293 were exposed to a mixtnre of both. Ho difference between the three groupa was identified and the observed impairment of lung function in some men was related entirely to the effects of smoking. However, measured personal exposures were not available for these men. A study of 8l& men currently and previously employed at a PVC manufacturing plant (SOUTAH et al.. 1980) in which estimates of personal exposure to PVC dust were based on detailed occupational histories and current measurements of dust levels in the factory showed a statistically significant reduction in tests of lung function among msn with the highest PVC dust exposure, and some of these men had small rounded opacities on their chest radiographs. The men with these radiological changes had significantly lower mean lung function test values than men whose films were considered to be normal. No relationship was found between exposure to PVC dust and impaired transfer factor for carbon monoxide. 1.2 The present study The present study was requested by Vinatex Ltd., and was carried out with the full agreement of management and workforce, and arose from their cone rn about some employe s whose lung function, particularly the Cm 007710 4. transfer factor for carbon monoxide, appeared to be abnormal. The transfer factor for carbon monoxide measures the ability of the lung to exchange gases between the inspired air and the blood. The study was designed to describe the distributions of various measures of lung function, including the transfer factor, in current and former employees at the PVC factory and to identify men with low lung function values. These men would be regarded as 'cases' and would be compared with two groups of controls, in order to examine possible associations between abnormally low lung function values and personal, occupational and environmental factors. Tho total survey population included the workforce of two factcries; one was the PVC factory of interest and the other was a large iron foundry situated a few hundred yards away. 1.2.1 The PVC factory The plant had been in operation since 1969 and for most of that time had produced suspension polymer. For a period of three years (1971 - 1974) emulsion polymer, which has a smaller particle size than suspension polymer, had been manufactured in one of the twc reactor buildings. During the manufacturing process vinyl chloride is pumped from the tank farm storage area via another storage tank to two reactor buildings. Under conditions of increased temperature and pressure and in the presenes of other substances acting as catalysts and surfactants, polymerization of VCM takes place. The resulting PVC is piped as a slurry to blending tanks and is then dried by centrifuging and rotary drying. The dried polymer is sifted and either removed to storage silos or bagged and stored in the warehouse before being dispatched. The manufacturing process is operated in batches throughout the 4 hours and the workforce is divided into four shifts. In the reactor and dryer buildings men usually start as 'B' operators and can then proceed to b 'A* operators and sometimes 'Lead' operators. , Available data suggest that prior to 1975 levels of VCM in the factory were considerably higher than the current low levels* During the period 19^9 - 1975 men working in the reactor' buildings, and particularly those involved in the manual cleaning of reactors, are likely to have been exposed to the highest 1 vels of VCM. CMA 007711 5 1.2.2 The foundry The foundry was situated near the PVC factory in the same industrial valley and manufactured moulded steel products. The manufacturing process involved the production of molten steel which was cast into appropriate moulds to which various finishing techniques were applied. CMA 007712 2. METHODS 2.1 Selection of the survey population All 177 men currently employed at the PVC factory were invited to take part. The names of another 263 men who had worked at the plant since it started production in 1959 were identified from factory records and attempts were made to trace and invite all these men using information supplied by the management, union representatives and local records. At the foundry the study was confined to 283 men selected randomly from the 1,085 current mala employees. 2.2 The medical survey The factories were visited by the medical survey team and men were 3een by appointment. Details of each man's smoking history were recorded by a trained clerk using a questionnaire which was a modified version of the smoking section of the Medical Research Counci] Questionnaire of Respiratory Symptoms (HRC, 1976) (see Appendix 1). A full occupational history was recorded for each man by a trained clerk who had previously visited both factories and was familiar with their layout and the manufacturing processes. Details of all jobs which a man had done since leaving school were recorded and the time spent in each of them noted. All PVC factory employees had measurements of forced expiratory volume in one second (FEV^), forced vital capacity (FVC) and gas transfer factor for carbon monoxide (Twco). For foundry workers, approval was ootained for measurement only of Tueo. Measurements of FEV1 and FVC were made using an electronic dry rolling-seal spirometer (Ohio 800). After a practice expiration, three forced expirations which were considered to be technically satisfactory from a maximum of six were recorded. The maximum values of FEVX and FVC, cot necessarily in the same breath, were used for the analysis, and the ratio of FEV1 to FVC was derived from thes figures. Cbf* 007712 7 Single breath gas transfer factor for carbon monoxide (Tuco) was measured by the breathholding method of MEADE et al. (1965) based on the modified Krogh technique. An automated spirometer/gas sampling system (Transfer Test B, P.K. Morgan Ltd., Chatham, Kent) was used and duplicate estimations were made for each man at least 10 minutes apart. Technically unsatisfactory tests were rejected and repeated (i.e. if the inspired volumes of the two tests differed by more than 1QS, if the spirograms of the manoeuvres were of different shape or if the rates of inspiration and expiration were too slow). The mean of the results of the two satisfactory tests was used in the analysis. Each man was weighed fully clothed and his standing height measured. 2.3 Methods of analysis The data were studied initially by summary descriptive statistics and multiple linear regression analyses of lung function taking into account age, height, weight and smoking habit. Subsequent examination of the standardised residuals* was carried out and on the basis of this cases and controls were selected. 2.3.1 Classification of smoking histories Men were assigned to one of three smoking categories; lifelong nonsmoker, current smoker and ex-smoker. No distinction was made in the analysis between type of smoking and the two 'smoker' groups included smokers of manufactured cigarettes, hand-rolled cigarettes, pipes and cigars, since the majority of msn smoked manufactured cigarettes. 2.3.2 Analysis of data from total survey copulation The distributions of lung function and various explanatory variables * A standardised residual, SR, is the difference between an observed lung function value and its predicted value from multiple linear regression analysis, divided by the estimated standard deviation of the unexplained variation from this model. i SR a (observed value - value predicted from fitted equation) (estimated standard deviation Vf "the prediction) cm 007714 1 8. were examined for systematic patterns amongst current and former employees of the PVC factory and current employees at the foundry. This was further explored for fwco and FEVt by multiple linear regression analysis taking account of age, height, weight and smoking. The relationship between a man's observed and predicted values was expressed as a standardised residual (SR). Thus men whose observed values were close to the predicted values would have SR values clustered around zero and correspondingly men with impaired lung function would hav the largest negative SR values. The distribution of SR values was examined to see if there was evidence of an unexpectedly large number of men with impaired lung function and if so, to examine if either PVC factory or foundry employees were over represented amongst these men. 3.3.3 Selaction of cases and controls For each lung function variable those men with the largest negative SR values were chcsen as cases. Two groups of controls were selected rendcmiy, firstly from those men whose SRs were clustered around zero and secondly from those with the largest positive SRs. 2.3.4 Case-control study Casas were initially compared with the rest of the survey population in order to identify systematic differences amongst related factors, e.g. age, smoking habit, employment status. 'The occupational and smoking histories of eases and controls were studied for systematic differences. Fisher's exact test, chi-squared tost for 2x2 contingency tables and chi-squared test for linear trend were used where appropriate. Classification of smoking and emnlovment histories Smoking histories were classified as they were for the total population (see Section 2*3.1). Additional information about the number of cigarettes smoked and age of starting- smoking was analysed in the easecontrol study. Bread occupational categories were defined for both PVC CMA 007715 9. factory and the foundry (Tables 1 and 2) and the total number of years spent by all cases and controls in each occupational category was calculated. Additional information was available for PVC employees in relation to exposure to emulsion polymer and employment in the factory prior to 1975* From the- full occupational history, the number of years in 'noxious' industries was recorded. 'Noxious* industries were classified into four groups; the coal and chemical industries have certain well recognized hazards, while the lung function of men in the steel industry has been reported to be lower than nan in non-dusty employment (HIGGINS, 1970); the fourth, designated 'other*, included industries iu which hazards could possibly arise although they would be less likely than those of the otner groups (see Appendix 2 for a list of 'other noxious' jobs). Employment of men in the manufacturing of ?VC other than at the PVC factory was also noted. CNrt 007716 ' 10, 3* RESULTS 3.1 Description of total aurvev population A total of 488 men was seen consisting of 165 current FVC factory employees (93# of those who were asked to participate), 102 PVC factory leavers (3^S of those who were invited) and 221 foundry employees (78$ of those invited). Three men (one from each employment category) did not complete the Two measurement and one foundryman did not have height and weight values recorded; the analysis was based on the remaining 484 men. FEV1 and FVC measure ments were not obtained from three FVC factory leavers and were not carried out on the 221 foundrymen and the analysis was based therefore on 264 men. 3*2 Analysis ef lung function data from total survey population 3*2.1 Calculation of predicted values and standardised residuals The effects of age, height, weight and smoking habit on the Tlco and FZV1 were studied in this population by multiple linear regression. The development of the regression model used is described in Appendix 3* Standardised residuals (SR) for Tlco and FSV1 were calculated for each man from the final regression model. Thus a man's standardised residual Tlco represents the amount by which his Tlco value differs from that predicted by his age, height, weight and smoking habit after standard isation. 3*2.2 .Distribution of standardised residual values of Tlco and F5V, for total survey population After allowing for the above factors, the standardised residual values of Tlco for the total survey population showed a symmetrical distribution, with no greater number of men in the negative tail of the distribution than would be expected to have occurred by chance. This indicated that there was no evidence that a substantial number of men had suffered a clinically Important reduction of their Tlco. However, for the FEVj SR distribution there were slightly more extreme negative values than extreme positive values (Figures 1 and 2). 3*2*3 Selection of eases and controls It was decided that about 30 cases would f m a study group of appropriate size. Th threshold S3 value for Tlco below which there was approximately this number of men, was - 1.5. giving }1 d n. A CMA 007717 .11 eontrol group of 31 men was selected randomly from those men with SB values between - 0.25 and + 0.75 inclusive (Tuco 'average' controls). A second control group of 31 'extra-healthy' men was selected randomly from those with SB values in excess of 0.75 (Tuco 'healthiest' controls). Similarly 30 men with an PEVj SB value of less than - 1.1 were selected as FSV1 cases and two control groups, each of 30 sen, were selected randomly from those with an SB value between - 0.25 and * 0.75 inclusive (FEVt 'average' controls) and from those with an SR value in excess of + 0.75 (PEVj 'healthiest' controls). 3*3 General features of cases, controls and the total surv*y population 3-3.1 Are, height and weight The mean age, height and weight of Tuco cases and controls, cases and controls and the total population are given in Tables 3 and 4. TLco cases and controls were of similar age but cases tended to be taller than the control groups. Although the mean ages of T<-co eases and control a*, groups were similar, study of the age distributions (Table 5) showed an j|j excess of current PVC factory employees in the 45 - 54 age group when / compared with both groups of controls and the rest of the population. ^ FEVl cases were slightly older and taller than the controls and the rest - of the population but there was no difference in the age distribution between employment groups or cases and controls. 3*3.2 Employment status and smoking habit The employment status of cases, controls and the total population is shown in Tables 6 end 7* PVC factory employees were slightly over represented amongst Tuco eases but this eould easily have occurred by chance. Differences in smoking habit are discussed in a later section. 3*3*3 Lurur function The mean values of Tuco for Tuco cases and controls and the total population are shewn in Table 3 and mean values of Tuco, FEVt and PVC for TEVi eases and controls are shown in Table 4. CMA 007718 12 Observed Tuco and FEVi values were expressed as a percentage of values predicted on the basis of Cotes's regression model (COTZS, 1979) and the distribution of these values for cases, controls and the total population are shewn in Tables 8 and 9* 3.4 Clinical description of Tuco cases and FEY, cases Fifteen men (nine FVC workers and six foundrymen) of the 31 Tuco cases had Tico values below 7CSS of their predicted values and four of these were below 6C5S (Table S). Nineteen of the 31 cases were from the PVC factory and of those, four ter. had FEY. values of less than 80S of their predicted value and low FEVl/FVC ratios indicating airflow obstruction. The remaining 15 men had FEVj, values within the normal range although further examination of their lung function data (forced expiratory flow-volume loops) suggested that seven of these might have mild airflow obstruction. Details of the 10 PVC workers with the lowest Toco standardised residual values are given in Table 10. Of the 30 FEVj, cases, 1J had observed values below 8C of their wedicted valuer and 10 of these were less than 7C8> (Table 9) The majority (10) of the 13 men with reduced FEVt had FEVi/FVC ratios below 7C& suggesting airflow obstruction. Seven of the FEVt cases were also selected as Twco cases.. 3.5 Ca3e-control study The occupational histories and smoking1 habits of cases and controls were comuarnd in order to explore the observed differences in their lung function ?.5.1 Occunatioral histories of cases and controls Analyses of the current employment status of cases and controls showed that PVC factory workers were slightly over-represented smongst the T*-co cases (Table 6), though this difference could easily have arisen by chance. The majority of PVC workers had worked in more than one type of job and in more than one broad occupational category during their employment with the company. Analysis of the mean duration of employment in each broad category failed t show any differences b tween T-co eases and their 007719 13. controls (Table 11), though more casas than controls had worked in Jobs in category 1, those occupations close to the pressure vessels where exposures to VCM were mostly likely to have occurred in the past. This difference could easily have occurred by chance, if ?VC workers alone are considered but if the foundrymen are included, 11 of J1 cases (35^) had worked in category 1 Jobs .in the PVC factory, whereas only 10 of 62 controls (16&) had done the same. The difference is significant at the 7Z level. These occupational differences were not apparent for the FE V,* cases and controls (Table 13). There was also movement between Jobs at the foundry but there were no differences in the pattern of employment cf cases and controls (Table 12). ?re-19'75 employment following the recognition of the hazards of VCM exposure in 1973, levels of VCM in the factory were progressively reduced during 197^ and by January 19?5 the exposure levels were low. The numbers of cases and controls who had been employed at the PVC fsotory before 1st January 1975 were compared. Seventeen of the 19 FVC worker Twco eases had been employed before 1975 compared with five of the 15 'healthiest' controls and 11 of the 13 average controls (Table I1*). Using a Xs tost for trend, there was strong evidence to suggest a significant increase in the proportion of men working before 1975 over 'healthiest' controls, 'average* controls and cases. Looking at comparisons between groups only the difference between cases and 'healthiest' controls was significant. Analysis of the duration of employment 0? men within different age groups showed that pre-1975 working was sees, in younger as well as in older men (Tables 15, 16, 17). Mo differences were seen in the number of men employed before 1975 between PVC factory FEVt cases and controls (Table 18). A similar analysis of foundry Tuco cases failed to show any relationship with pre-1975 employment (Table 19). In conclusion there is evidence to suggest that employment at the PVC factory before 1975 was associated with impairment of Tuco. CMA 007720 14 Exposure to emulsion polymer The employment of eases and controls in the manufacturing of emulsion polymer was studied and compared. Ho man had been exclusively involved in the production of emulsion polymer so men were divided into three groups; those who had worked with suspension polymer only, those who had worked with both suspension and emulsion, and thosa who had not been exposed to either. Similar proportions of "Leo eases and controls (Table 20) and FEV1 cases and controls (Table 21) are represented in each IStof these three groups. There is no evidence that exposure to emulsion ^Sfpolymer adversely affected the lung function of those who worked with git. Frevious employment in other industries There was no evidence that the observed differences between eases and controls could be explained on the basis of previous employment in industries other than the PVC factory or the foundry. Ho differences were found either in the numbers of cases and controls or in the mean numbers of years spent by them working in other industries which might be considered noxious (l.e* coal, steel, chemicals and 'others') (Tables 22, 23, 24). No men had been employed in the manufacturing of PVC outside this PVC factory. 3.5*2 Smoking habits of cases and controls A higher proportion of Ti-co eases (65$) were current cigarette smokers than were either group of controls (4&) or total survey population (403) (Table 25). This difference was not seen between the T&fl eases and controls but there were more ex-smokers among the TEVr cases than there were among the controls (Table 26). The smoking histories were examined in greater detail by analysing the number of cigarettes which current cigarette smokers smoked daily both on weekdays and during the weekend, the number smoked by each man during the maximum smoking period of his life and the age at which each man started smoking. There was no significant difference in the number of cigarettes smoked on we kdays between both groups of cas s and the'healthiest* controls (see Figures 3 and 4), and similar results were found for 'average' controls. CHA 007721 Analysis weekend smoking showed that more Tlco cases smoked 25 or more cigarettes per day than did the Tlco healthiest controls (Figure 5). N'o such difference was found to exist with average controls. Comparing the weekend smoking habits of FVC factory and foundry Tlco cases, it was found that a larger proportion of foundrymen smoked mere than 25 cigarettes per day (Figure ?) For the FEVj men, more cases than average controls smoked 25 or more cigarettes per day at weekends. This difference was not seen between cases and healthiest controls. Consideration of the number of cigarettes smoked during a man's maximum smoking period showed that of the men at the PVC; factory, five of the 13 Tlco cases, compared with rone of the six Tlco'healthiest' controls had smoked a maximum of 25 or more cigarettes por day (Figure 6). but this difference in proportions could easily have arisen by chance. The age at which men started smoking was also examined. There were significant differences between cases and controls. Of the 20 Tlco eases who were current smokers, eignt had started smoking by she age of 15 compared with one out of the 14 'healthiest' controls and 16 had started by the ace of 16 compared with five out of the it 'healchiest' controls (Fizure ?a), while the figures for average controls were that six out of 15 had started smoking by the age of 16 (Figure ?b). Of the 13 FEVi cases who were current smokers, seven had started smoking by the age of 16 compared with two of the 11 'healthiest' controls (Figure Qa). These differences were not seen between cases and 'average' controls (Figure 9b). In conclusion Tlco cases and 'healthiest' controls and FFV1 eases and 'average' controls differed in the number of men smoking 25 or more cigarettes per day at weekends. A, similar difference was found between Tlco cases at the PVC factory and the foundry. In general, cases started smoking at a younger age than controls. Cldft 0077 16 4. DISCUSSION The present study had two aims. First, to describe the lung function, particularly the Tlco, of current and past employees of a factory manufacturing PVC, and seek evidence of a possible excess of men whose Tlco was abnormally low. Second, to examine the relationship between Tlco and occupation and other personal and environmental factors by a case-control study, in which the cases were men with lowest gas transfer factor after allowing for age, height, weight and smoking habit. Men from a nearby foundry were included in the study in order to increase the number of men with low or no exposure tc possible respiratory hazards at the PVC factory, but who were exposed to similar environmental conditions outside their workplace. In all 265 non from the 7VC factory and 219 men from the foundry were included in the Tlco analysis. he Tlco residuals among this combined population conformed approximately o a Normal distribution after allowing for age, height, weight and smoking abit, and did not suggest an undue excess of extremely low values. This ndicated that it was unlikely that a substantial number of men in the hole population were suffering from a clinically important reduction of he Tlco. In the case-control study the 31 men with the lowest Tlco after allowing for age, height, weight and smoking habit were selected as 'cases'. This does not imply that all 31 were suffering from lung disease, but among them were 15 men whose Tlco was less than 70S of the value predicted by published normal values, a level which would generally be regarded as abnormally low. Among the 19 eases at the PVC factory the pattern of lung function accompanying the low Tlco was that of definite airflow obstruction in four men, and possible airflow obstruction in another seven men, suggesting the presence of emphysema. The remaining eight men did not have evidence of airflow obstruction or reduction of their lung capacity (vital capacity). This pattern is unusual in clinical practice, and may possibly reflect pulmonary fibrosis or disturbances of the blood flow in the lungs. The degree of reduction of transfer factor of carbon monoxide end associated airflow obstruction might have been sufficient to cause breathlessness on exertion in some of these men. CM* 007723 1 17 The possible contribution of occupation in causing these lung function abnormalities was examined by comparing the occupational histories of the cases with those of controls. Two groups of controls were selected; one group from men with values of gas transfer near the mean for this population; the other group from those with values towards the high end of the range ('average' and 'healthiest' controls). The reasons far choosing two such groups were that men with near average values may have included some whose lung function had been slightly affected by noxious influences, while those with very high values were least likely to have been affected by noxious influences, but also could conceivably include men who were highly resistant to these influences, and would therefore not be suitable for the comparisons .iw.de in this study. The PVC workers were slightly over-represented among the cases with low Tlco, though this difference could easily have arisen by chance. Hen who had worked on jobs at the PVC factory which were close to the pressure vessels where exposure to VCM was most likely to have occurred in the past, were also slightly over-represented among the cases, and this difference approached statistical significance at conventional levels. There was, furthermore, an association between low gas transfer factor and a history of having workod at the PVC factory before 1975. This date is important because it was at this time that, in the light of information about some of the potential hazards of VCM, exposure to this gas was drastically reduced. This association between low gas transfer, factor and working before 1975 was demonstrated by comparison with the 'healthiest* controls, the 'average' controls showing an intermediate pattern of association not statistically significantly different from the cases. This association with working before 1975 waa not found among foundry workers. This conjunction of findings suggests that an unknown environmental orj personal factor or factors associated with working at the PVC factory before 1975 might have been responsible for some impairment of the gas] transfer factor in some of these men. The most obvious candidate for suspicion is VCM, exposures to which are known to have CMA 00772A ig m m s M * i8. ^been much higher than post-1975 levels. Some support for this is provided by published case reports of VCX .workers with impairment of gas transfer factor, but proof of association has been lacking (LAIIGE, 1975; DAItKE, 1976). though it is possible that many workers throughout the factory were exposed to a lesser degree. It is also possible that exposure to respirable FVC dust may have contributed to the low gas transfer factors, for this dust has been shown in other studies to be associated with impairment of other aspects of lung function (though not the gas trarsfer factor) and slight chest radiographic abnormalities (KASTfcANGELO et_ al., 19^9; SCtITAS et al., 1fl0). There was no evidence to suggest that a current risk to respiratory f health exists at either the PVC factory or foundry. ^Some differences m smoking habit were found between cases and controls JSnon-smokers being slightly commoner among controls, and heavier 3mok*rs fijslightly commoner among the cases. The cases tended to start smoking at a slightly younger age. We do not know if these small differences in smoking habit were sufficient to account for the reductions of gas transfer factor in the cases, but they would seem unlikely to account for the whole of the differences between cases and controls. While the response rate among currently employed workers was excellent, that for those men who had left the FVC factory was low (35K). If th men not examined had included either ar. exdess or deficiency of men with impaired gas transfer factor compared with the population examined', then the analysis of the distribution of values among the population seen could be unrepresentative to that extent. A similar analysis for another lung function test, forced expired volun in one second, was carried out for the PVC workers only. While some men did have impairment of this test result as would be expected in an industrial population of this kind, no associations with occupation could be demonstrated. CMA 007725 19 5. CONCLUSIONS AND HLCCHMSNDATTCNS We found no evidence of an unexpectedly large number of men with impairment of their lunr gas transfer factor among either PVC factory or foundry employees. There was, however, a snail number of men in both factories 'with impairment of their transfer factor. This could not be 3hown to be associated with current working conditions at either factory, but the pattern of results among PVC workers suggested that there was an association between impairment of the gas transfer factor and a hiatory of working in the PVC factory before 1975. There was also evidence that heavy smoking was associated with impairment of gas transfer. These findings give seme support to the hypothesis that work in the PVC factory before 1975 involved exposure to a substance that caused impairment of lung function in a small number of men. The results suggest that more detailed studies of the importance of exposure to vinyl chloride monomer, polyvinylchloride, smoking habit and other possible factors in causing impairment of lung function would be desirable, togther with a clinical assessment of the extent of lung damage in selected men. 007726 20 ACKNOWLEDGEMENTS This study was carried out with the full co-operation of the management and workforce of Vinatex Ltd., to whom we are grateful for financial support. We also thank the management and workforce of the foundry for their generous co-operation in the study. 00772? CM* 21 REFERENCES AGARWAL DK, KAW JL, SRIVASTAVA SP, SETH PK (1978) Some biochemical and histopathological changes induced by polyvinyl chloride dust in rat lung. Environmental Research; 16: 333 - 341. ARNAUD A, PCMMIER de SANTI P, GARBE L, PAYAN H, CHAEPIN J (1978) Polyvinyl chloride pneumoconiosis. Thorax; 33s 19 - 25. CHIVERS CP, LA'dRENCE-JONES C, PADDLE GK (1930) Lung function in workers exposed to polyvinyl chloride dust. British Journal of industrial Medieine; 37: l4> - 151* COPDIER JM, FIEVE2 C, LEFSVRS M-T, SEVRIH A (1966) Acroostcolyse et lesions cutar.aes associles chez deux ouvriers affeetees au nettoyage d'autoclaves. Cahiers de Kedecine du Travail; 4: 14 - 19. COTES JE (1979) Lung function. Oxford: Scientific Publications: 369 - 385* Blackwell CREECH JL, JCENSCN MN (1974) Angiosarcoma of liver in the manufacture of polyvinyl chloride. Journal of Occupational Hedieine; 16: 150 - 1?1. OASIS CS (1976) Vinyl chloride and the production of ?VC (Discussion). Proceedings of Royal Society of Medicine; 69: 280. FRONGIA N, SPINAZZOLA A, BtJCAKELLI A (1974) Lesioni polmonari sperimentali da inalazione prolungata di PVC in embiente di lavoro. Medicina del Lavoro; 6$: 321 - 342. GAMBLE J, LIU S, McMICHAEL AJ, WAXWEILEH RJ (1976) Effect of occupational and nonoccupational factors on the respiratory system of vinyl chloride and other workers. Journal of Occupational Medicine; 18: 659 " 670. HIGGINS ITT (1970) Occupational Factors in Chronic Bronchitis and Emphysema. Review. In: Orle NGM, Van Der Lende R, eds. Bronchitis III. Proceedings of the Third International Symposium on Bronchitis at Groningen, The Netherlands. Springfield (HI.): Charles C. Thomas, 1970 : 83 - 99. CMC 007728 22 LANGE CS, JlfSE S, STEIN G, VELTMAH G (1973) Die aogenannte Vinylchlorid-Krankheit - eine berufsbedir.rte Systemsklerose? International Archives of Occupational Health; 32: 1 - 32. LIUS R, ANDERSON H, NICHOLSON WJ, DAUM S, FISCHBEIN AS, SELIKOFF IJ (1975) Prevalence of disease among vinylchloride and polyvinyl chloride workers. Annals of New York Academy of Science; 246: 22 - 4i LIUS R, ANDERSON H, HILLER A, SELIKOFF IJ (1976) Pulmonary changes among vir.yl chloride polymerisation workers. Chest; 69: (Suppl. 2 Feb.), 299 - 303. MASTHANGELO G. HANNC M, MARCER G, BAETCLUCCI GO, GEHIGNANI C, SALADINO G, SIMONATO L, SAIA B (1979) Polyvinyl chloride pneumoconiosis: epidemiological study of exposed workers. Journal of Occupational Medicine; 21; 540 - 542. MEADS F, SAUNDERS MJ, HYETT F, REYNOLDS JA, PEARL N, COTES JE (1963) Automatic measurement of lung function. Lancet; 2: 573 - 575. MRC (1976) Medical Research Council Working P**ty on Research into Chronic Bronchitis. Publications Group, Medical Research Council, 20 Park Crescent, London WIN UAL. KILLER A, TEIRSTEIN AS, CH&ANG M, SELIKOFF IJ (1975) Changes in pulmonary function in workers exposed to vinyl chloride and polyvinyl chloride. Annals of New York Academy of Science; 246; 42 - 52. PRODAN L, SUCIU I, PISLARU V, ELEA E, PA30U L (1975) Experimental chronic poisoning with vinyl chloride (monochloroethane). Annals of New York Academy of Science; 246; 159 - 163. SOUTAR CA, COPLAND LH, THORNLEY PE, HURLEY JF, OTTER? J, ADAMS WGF, BENNETT B 0980) Epidemiological study of respiratory disease in workers exposed to polyvinylchloride dust. Thorax; 35* 644 - 652. SICIU I, DREJMAN I, VELASXAI M (1967) Study of disease caused by vinyl chloride. Medicina del Lavoro; 58: 261 - 271. CMA 007729 23 VELTMAN G, LANGE CE, JURE S, STEIN G, BACHNER 0 (1975) Clinical mans festations and course of vinyl chloride disease. Annals of New York Academy of Science; 2^6: 6 - 17. VERTKIN YI, MAMONTOV YR (1970) The state of the bronchi and lungs in workers employed in the manufacture of polyvinyl chloride articles. Gigiena Truda i Professional 'nye Zabolevaniya; 1^: 29 - 32. CMrt 007730 TA3LE 1 25 Classification of all ;jobs at Vinatex into six broad occupational groups. Broad occupational group Jobs included In group 1 All nen worising in reactors 1 and 2 * 2 Dryer zoos 3 operators * * 3 Dryer zoon Lead., A and A/3 operators 4 Warehousemen, maintenance staff, laboratory staff and drivers *** 5 General stafi who visit plant, e.g. shift supervisors and foremen 6 Management and office staff * These men are mo(*t likely to have been exposed to high concentrations of VCM in the past. * These men are involved in the bagging of PVC and are probably exposed to higher concentrations of dust than other workers in the dryer buildings. "* These men are potentially exposed to all raw materials and products. 007731 TABLE 2 Classification of foundry jobs into seven broad occupational groups Occupational group No. Descrintion Jobs included in group 1 Furnace and melt: furnace operator, burnir, charger, weirher, skimmer, smelter, sla^man, ladle repairer, concrete liner. 2 Sand and blasting: coremaker, sand tester, sand mixer, shot blaster, core stripper, knock-out, brick maker. 3 Metalwork: driller, grinder, blacksmith, tinsmith, wagon repairer, rope splicer, cupola repairer, maintenance fitter's mate, maintenance fitter, turner, trainee in the training centre, borer, saw renairer, wagon reoairer, milling operator, inspector in machine shop, welder. 4 General and other: labourer, patternmaker, plater, platelayer, pine loader, crane driver, driver, cleaner, technician, trainee, pine roller, slinger, quality control, joiner, greaser, inspector, saddler, bricklayer, core inspector, desnatcher, hydraulic attendant, shunter, plumber, pipe recorder, runner operator, sawyer, staff, power house attendant, canteen, tool room attendant, electrician, storeman, ore crusher, ram driver, safety officer. 5 Paint and dipping: dipper, paint sprayer, painter and decorator. 6 Casting: caster, manhole maker, socket man, machine moulder. 7 Fettler: fettler TJLBLE 3 27. Features of Tino cases, controls and total survey population. Mean (and standard deviations) of age, height, weight and Tlco. Humber of men Cases 31 Tlco Grouos ControIs Controls (average) (healthiest) 31 31 io .a-. survey population 484 Age Cyra) 41.8 (SB) (10.2) 42.3 (12.5) 40.3 (11.3) 42.2 (11.9) Height (csts) Mean 176.1 (SD) (7.1) 174.0 (6.6) 173.9 (5.6) 173.8 (7.0) Weight Clcffa) Mean 32.7 (SD) (13.3) 34.9 (18.5) 79.2 (9.5) 30.2 (12.6) Tlco (ml/min. mm Eg) Mean (SD) i 22.2 (4.1) 31.8 (2.9) 37.3 (4.3) 30.5 (5-9) CMA 007733 TA3LE 4 28 Features of FZ7t cases, controls and total survey population* Mean (and standard deviations) of age, height, weight, Ttco, FEVj and FTC. Number of nen Cases 30 Tlco Groups Controls Controls (average) (healthiest) 30 30 Total survey population 264 Age (yrs) Mean 43.3 (335) (11.0) 41.3 (12.5) Height (cns) Mean 176.0 (SB) (7.4) 174-5 (6.6) Weight (kgs) Mean 82.2 (SB) (13.3) 78.4 (10.1) FEVj (litres) Mean (SB) 2.7 (0.7) 3.9 (0.7) FTC (litres) Mean (SB) 4.1 (0.9) 5.1 (0.8) TlCO Mean (ml/nin..in2g) (SB) 29.1* (6.8)* 32.3 (6.0) 42.1 (12.0) 175.9 (8.0) 80.4 (11.5) 4.5 (0.8) 5.9 (0.9) 31.3 (6.5) 42.2 (11.8) 174.3 (7.1) 30.4 (12.3) 3.7 (0.9) 4.9 (1.0) 30.5** (6.1)** * Value baaed on 29 observations. ** Value based on 262 observations. 007734 ,400 *W3 TABLE 5 Age dlatribution of Tuco cases and controls and the total survey population by eaployaent status. CASES PVC current sen PVC leavers Foundryaen Age ranges in years 0 - 24 25 - 34 35 - 44 45 - 5** 55 - 64 65+ Total 1 46 11 222 1 1 8 1 434 12 AVEHAGE CONTROLS PVC current sen PVC leavers Foundryuen 141 3 1 12 3 2544 9 4 18 HEALTHIEST CONTROLS PVC current aen PVC leavers Foundryaen 2 324 1 12 1 2643 12 3 16 TOTAL POPULATION PVC current aen 9 37 57 35 26 0 164 PVC leavers 4 24 33 19 11 10 101 Foundryaen tn 17 48 50 6o 44 0 219 3 TABLE 6 30. Eaployment status of Tuco cases, controls and total surrey population. Number of men in each eaployment group with percentages- in brackets. Four men excluded, see text. PVC Current Workers Total surrey population 164 PVC Leavers 101 Foundry 219 Total 464 Casas Controls (average) Controls (healthiest) All 11 ( 34) 8 ( 53) 12 ( 26) 9 ( 28) 4 ( 27) 18 ( 39) 12 ( 33) 3 ( 20) 16 C 35) 32 (ICO) 15 (100) 46 (100) 31 31 31 93 TABLE 7 Employment status of FEVt cases, controls and total surrey population. Number of men in each eaployment group with percentages in brackets. Three men excluded, see text. Rounding error of percentages not adjusted to justify totals. - PVC Current Workers Total survey population 165 PVC Leavers 99 Total 264 Cases Controls (average) Controls (healthiest) All 14 ( 26) 18 C 34) 21 ( 4o) 53 Ooo) 16 C 43) 12 C 32) 9 ( 24) 37 (100) 30 30 30 90 CMA 007736 TABLE 8 Distribution of observed Tiro an a percentage of predicted Tlco using Co tee'a regression model for non-onokera. Numbers of men (percentages in brackets) for the oases, two control groups and total survey population. Cases < 69 Controls (average) Controls (healthiest) Total survey population Tlco % predicted Total 50- 59 60 - 69 70 - 79 80-89 90 - 99 100 - 109 110 - 119 ^ 120 4 (12.9) 11 12 (35.5) (38.7) 4 (12.9) 31 11 13 7 31 (35.5) (41.9) (22.6) 3 (9.7) 14 (45.2) 14 31 (45.2) 4 (0,8) 14 (2.9) 29 (8.0) 75 114 (15.5) (23.6) 82 (16.9) 46 484 (9.5) CM o^ cm CMA 0 0 7 7 3 7 TABUS 9 Distribution cf observed FEV. aa a percentage of predicted P2V, using Cotes's regression nodal for non-amokera. ihuobern of non (percentages in brackets) for the cases, two control groups ani total survey populution. $ *19 FiSV, % predicted 50-59 60 - 69 70 - 79 80-89 90 - 99 100 - 109 110 - 119 ^ 120 A u Let X. Cases 1 (3.3) * (13.3) 5 (16.7) 3 14 (10.0) (46.7) 3 (10.0) 30 Controls (average) 3 17 (10.0) (56.7) 9 (30.0) 1 (3.3) 30 Controls (healthiest) 1 (3.3) 6 23 (20.0) (76.7) 30 Total survey 1 population (>.<) H ( 1.5) 6 (2.3) 9 29 (3.4) | (11.0) 48 74 (>0.2) (28.0) 47 46 07.0) (17.4) 264 TABU Deteila of the 10 PVC factory Tioo easee with tha lowest atandardited rasidual valuaa of T-co. Caaa No. 1 did not complete tha aplrooetry task. Predicted values ara for non-saokere (Cotaa, 1979). Aga Bo. Sacking oataaonr SR Tt-ca Tvco `h-eo % FEfj litres 7EV, litres m TEv (observed) (predicted) predie tad (observed) (predicted) predicted litres m*100 1 30-3*1 0 - 2.89 20.1 34.6 *8.3 - - - -- 2 65 - 69 - 2.75 14.1 27.4 51.3 2.1 3.0 69.8 3.8 55.2 3 35 - 39 C - 2.22 20.1 31.8 63.3 3.6 3.8 95.2 5.2 68.9 S 40-4*1 s - 2.15 20.9 30.5 68.4 . 1.2 3.3 34.3 3.5 35.1 5 35-39 Q - 2.11 20.8 32.1 64.6 3.2 3.8 84.9 4.1 77.9 6 55-59 G - 2.02 14.7 23.9 61.4 2.6 2.7 95.5 3.3 77.9 7 505*i a 2,01 15.4 25.9 59.5 2.7 3.0 90.6 4.3 62.2 8 35 - 39 c 9 45 - 49 10 50 - 5** N C - 1.99 23.3 - 1.92 - 1.84 22.5 18.8 35.5 29.2 29.0 65.6 77.0 64.8 4.2 4.1 3.6 4.1 101.7 5.7 74.3 3.4 120,1 5.1 8o.o 3.3' 107.9 4.7 75.8 Tha abbreviations of aaoklog categorise ara aa follows! C a currant aaok t>r Ex-oeoker Ttto unit* ara al/ain, a Bg. 2 b life-long non-eeoker CMA 0 0 7 7 3 9 TABLE 11 PVC factory Ttco cases and controls. Kean tines (years) spent in each occupational group with number of men in brackets. See Table 1 for key to occupational groups. Amongst these cases and controls, the only man who had spent time in occupational group 6 was a current employee, selected as one of the 12 'healthiest' controls. He had spent 1.7 years in this group. CASES Current men Leavers Number of men 11 8 AVERAGE CONTROLS Current men Leavers 9 4 EEAITSTEST CONTROLS Current men Leavers 12 3 1 3.7 (6) 1.6 (5) 9.1 (5) 0.7 CD 3.3 (5) 1.5 (D . Occupational groups 2 34 5 C.4 6.1 9.0 9.7 (5) (3) (4) (2) 0.8 ii.8 (6) (1) to - i.i 6.8 7.1 12.3 C3) (D (4) (D 0.4 (4) - 1.8 <D to 1.2 10.8 7.3 3.3 (8) (D (2) (2) 0.5 (3) to - * CMA 007740 TABLE 12 Foundry Tlco cases and controls. Mean tines (years) spent in each occupational group with number of men in brackets. Bee Table 2 for key to occupational groups. Number of men 1 Occupational groups 2 345 S7 CASES 12 7.3 3.0 12.3 4.0 3.2 11.4 1.0 (4) (2) (5) (7) (2) (2) (1) AVERAGE comoLs IS 4.6 16.1 30.4 (3) (5) (1) 9.4 (9) . 7.4 (1) 10.S (5) 2.5 (1) EEA1THXEST COMEECLS IS 13.4 C5> 4.5 (3) 12.7 (3) - 12.5 (8) 11.6- (6) - TABLE 13 PVC factory FS^ cases and controls. Mean times (years) scent in each occupational group with number of men in brackets. See Table 1 for key to occupational groups. . Number of men 1 CASES Current men Leavers 14 5-5 (7) 16 2.1 (8) AVERAGE CONTROLS Current men Leavers 18 3.2 (10) 12 1.3 . (5) HEALTHIEST CCCTROLS Current men 21 6.4 CIO) Leavers 9 1.2 (2) Occupational groups 2 34 5 1.3 4.3 (8) (2) 0.8 4.7 (9) (3) 6.1 6.8 (6) (2) 1.0 - (2) -1.2 (10) 0.9 (7) 5.2 (1) 4.1 (3>- 7.6 7.7 (5) (2) 1.2 - (3) 1.2 (10) 0.3 (6) 0.7 (2) - 7.2 3.6 (9) (3) 2*1 (2) 6 3.8 (1) - 5.0 (2) 3.1 (2) 2.6 (2) 1 -1 36 TABLE 14 For Tuco analysis, the distribution of numbers of FVC cases and controls who had worked at the ?VC factory before 1975 and only after 1975* Pro 1975 Post 1975 Total Cases 17 2 1 Average Healthiest Controls Controls 11 5 2 10 13 15 Total 33 l4 47 TABLE 15 PVC factory Ttco cases. Number of men within each age group and duration of pre-1975 employment category. Tima of employment Duration of employment 0-24 25 - 34 Age (yrs) 35-44 45 - 54 55 - 64 ----------- [ i Total 65 + Pre 1975 Post 1975 Total < 2 yr 2 - 4 yr > 4 yr - 1 1 1 34 12 4 1 26 8 19 3 15 2 1 1 19 CMA 007742 37 TABLE 16 PVC factory Tlco average controls. Number of men within each age group and duration of pre-1575 employment category. Tima of IXiration of Age (yra) aoployment employment 0-24 25-34 35-44 45 - 54 55 - 64 65 Total Pre 1975 f < 2 yr j 2 - 4 yr [ > 4 yr Post 1975 Total - '1 1 2 21 1 12 11 2533 4 3 4 2 . 13 TABLE 17 PVC factory TLeo healthiest controls. Number of men within each age group and duration of pre-1975 employment category. Time of Duration of employment employment Pre 1975 Post 1975 Total < 2 yr < 2 - 4 yr > 4 yr - 1 2 3 CM 1 O 25 ~ 34 Age (yrs) 35-44 45-54 55 - 64 -- Total 55 - 1 1 11 323 5241 2 4 2 10 15 CMA 007743 38 TABLE 18 For FEVj, analysis, the distribution of numbers of PVC cases and controls who had worked at the PVC factory before 1975 and only after 1975- Pre 1975 Post 1975 Total Cases 23 7 30 Average Healthiest Controls Controls 18 19 12 11 30 30 Total 0 30 90 TABLE 19 For Two analysis, the distribution of numbers of foundry eases and controls who had worked at the foundry before 1975 and only after 1975- Pre 1975 Post 1975 Total Cases 8 4 12 Average Healthiest Controls Controls 13 12 54 18 16 Total 33 13 46 CMA 007744 TABLE 20 39 For Tlco analysis, the distribution of PVC factory cases and controls who had worked with different polymers* Cases Average Controls Healthiest Controls Total Emulsion and suspension Suspension only Neither suspension cor emulsion 6 9 4 8 4 18 3 11 23 2 06 Total 19 13 15 47 TABLE 21 For FE^ analysis, the distribution of PVC factory cases and controls who had worked with different polymers* Bmlsion and suspension Suspension only Neither suspension nor emulsion Casas Average Controls 87 18 13 4 10 Healthiest Controls Total / 10 25 13 44 7 21 Total 30 30 30 90 CMA 007745 TABLE 22 40 PVC factory Tteo cases and controls. Number of men who have worked in noxious occupations with mean umber of years spent by these men in brackets. See Appendix 2 for list of 'other' noxious occupations. CASES Number of men 19 AVERAGE CONTROLS HEALTHIEST CONTROLS 13 15 Steel 8 (5.5) Noxious occupations Chemicals Coal t (1.9) 7 (10.1) 03 6 (9.6) (6.9) 3 (6.1) 0 mm 2 (17.4) Other 8 (11.5) 7 (iO.l) 8 (7.1) TABLE 23 PVC factory FEV. cases and controls. Number of men who have worked in noxious occupations with mean number of years spent by these men in brackets* See Appendix 2 for list of 'other' noxious occupations. CASES Number of men 30 Steel Noxious occupations Chemicals Coal 10 (4*8 ) 5 (4.0) 16 (15.7) Other 16 (13.2) A7SSAGE CONTROLS 30 7 6 9 15 (9.8) (14.0) (6.3) (7.5) HEALTHIEST 30 4 CONTROLS (17.8) 4 (9.1) 11 (13.6) 18 (8.9) CMA 007746 TABLE 24 Foundry Tlco cases and controls. Number of men who hav worked in noxious occupations with mean lumber of years spent by these men in brackets. See Appendix 2 for list of 'other* noxious occupations. Number of men Steel Noxious occupations Chraieals Coal Other CASES 12 1 (3.0) 0 (0.0) 3 (5.4) 5 (1*3) AVERAGE CONTROLS 18 2 (9.6) 0 (0.0) 4 (9.0) 8 (10.9) HEALTHIEST comois 16 2 (4-7) 0 (0.0) 5 (2.9) 5 (7-2) CMA 007747 TABL2 25 ta Smoking habits of Tteo eases, controls and total survey population. Number of men in each smoking category with percentages in brackets. NonSmoker Current Smoker Ex-Smeker Total Cases 3 (9.7) 20 (64.5) 8 (25.8) 31 Controls (average) 4 (12.9) 15 (48.4) 12 (38.7) 31 Controls (healthiest) 7 (22.6) 15 (48.4) 9 (29-0) 31 Total survey population 109 (22.5) 234 (48.4) 141 (29-1) 484 TA3LE 26 Smoking habits of 7STl cases, controls and total survey population. Number oj. men in each Miink-tng category with percentages in brackets. Cases Controls (average) Controls (healthiest) Total survey population NonSmoker 5 (16.7) Current Smoker 13 (43.3) 7 (23.3) 15 (50.0) 9 (30.0) 12 (40.0) 59 (22.3) 125 (47.4) Ex-Smoker Total 12 (40.0) 30 8 (26.7) 30 9 (30.0) 30 80 (30-3) 264 CMA 007748 ^3 CMft 007749 Number of men m ^ m m h o h m w ^ cn o *5. PVC factory Fig, 3 Number of cigarettes smoked on weekdays by FEV1 cases and 'healthiest' controls who are current smokers. Number of men Fig. 4 Number of cigarettes smoked on weekdays by Tlco cases and 'healthiest' controls, at the PVC factory and the foundry, who are current smokers. CMrt 007750 47 >> t o u i t x j i o i ^ u to m Fig. 5 Number of cigarettes smoked per day at weekends by Tlco cases and 'healthiest' controls, at the PVC factory and the foundry, who are current smokers. CMA 007751 fc9. 87- 6* 5<eU 43- l 2* u 1- <33 AT B0 7a V7. 2 10 20 30 40 50+ 2- 1 p --^^-- 0 PVC factory _ Foundry Cases No. of cigs. 'Healthiest* controls. - Fig. 6 Maximum number of cigarettes regularly 3mcked per day by Ttco cases and 'healthiest* controls, at the PVC factory and the foundry, who are current smokers. Number of men Fig. 7 Maximum number of cigarettes regularly smoked per day by FEV^ cases and 'healthiest' controls. CMA 007752 51 (a) (b) Number of men F!g. 8 a) Age when started smoking cigarettes, for 'I\ co cases and 'healthiest' controls at the PVC factory and the foundry, who are current smokers. b) Age when started smoking cigarettes, for TVco cases and 'average' controls, who are current smokers. (a) (b) 5. 0 PVC factory g* 0 PVC factory 4- - 3* 1 2` S 1 _ *8 ______ Cases 1 1* P27 3 71 $ ' Cases i 0 <14 151617 1819 20 21 * Age (yvs) 0 < 14 B 1617 1819 20 21 + Age(yrs) 3 1. 2 2- 3- 4- '//S/MYX 'Olj.A ^ cJ Healthiest' controls iz 2- 34. m, a lA 'Average' controls Fig. 9 a) Age when started smoking cigarettes, for FEV. cases and 'healthiest' controls, who are current smokers. b) Age when started smoking cigarettes, for FEV. cases and 'average' controls, who are current smokers. CMA 007753 53 APPENDIX 1 SMOKING CUESTIONNAIFE 1 Do you smoke? If NO la Hava you ever smoked as much as one cigarette a day (or one cigar a week or an ounce of tobacco a month) for as long as a year? If NO to both carts of question 1, emit remaining questions on smoking. 2 How old were you when you started smoking regularly? 3 How old are you now? 4 Do (didj you smoke manufactured cigarettes? If YES 4a How many do (did) you usually smoke per day onweekdays? 4b How many do (did) you usually smoke per day at weekends? 4c What was the greatest number of cigarettes youever smoked regularly per day? 4d For how long were you smoking that many? 4e Since starting smoking tobacco have there been periods during which you did not smoke cigarettes? If YES, for how long altogether were you not smoking cigarettes? 4f (Apart from those times) what was the least number of cigarettes you ever smoked regularly per day? 4g For how long were you smoking that many? 5 Do (did) you smoke hand-rolled cigarettes? If YES 5* How much tobacco do (did) you usually smoke per week in this way? CMrt 007754 APPENDIX 1, page 2 5*. 6 Do (did) you smoke a pipe? If YES 6a How much pipe tobacco do (did) you usually smoke per week? 7 Do (did) you smoke small cigars? If YES 7a How many of these do (did) you usually smoke per week? 8 Do (did) you smoke other cigars? If YES Sa How many of these do (did) you usually smoke per week? For ex-smokers: 9 When did you last give up smoking? CMA 007755 55 APPENDIX 2 NOXIOUS OCCUPATIONS In the classification of noxious occupations the following jobs were included in the category 'other'. Although it is recognized that some of the jobs included in this category are not widely recognized as 'noxious', it was considered that they say on occasions be associated with health hazards and should therefore be included in the classification of noxious occupations Brewing Baker Flour miller Farm worker Wood cutter/sawmill worker Construction worker Bricklayer Plasterer Quarryman Paper mill worker Electrician Joiner Glassworker - Welder Scrap bnrner Foreman Coking plant worker Furnace operator Car body reoairer Paint sprayer Peinter/decorator Tarmacadam exposed workers CMA 007756 APPENDIX 3 Develorner.t of the multiple linear regression model used in the analysis of the data from the total survey copulation Preliminary multiple linear regression analysis indicated the anticipated relationship between Tweo and age, height and weight and between FEY! and age and height. These relationships were looked at again after allowing different intercepts and age slopes for non-smokers and all smokers whether current or ex-smokers. For the Tlco analysis, this was a significant improvement in the amount of variation explained. However, this group of smokers did not have a significantly lower mean Tlco after age, height end weight had been taken into account than non-smokers and the age slopes were similar. The model used for Tlco (but not the FEVl model) was further improved by introducing different intercepts and age slopes for three categories of smoking, non-smokers, current smokers and ex-smokers. This analysis showed that for ex-smokers the mean value of Tlco was significantly higher than that of current smokers (P < 0.05) hut that they experienced a greater loss of Tlco with age than current and non-smokers although these differences were not statistically significant (Table 1). Further expansion of this model by allowing different intercepts and age slopes for -the different employment categories (current and former employees at the PVC factory and foundry employees) within the three smoking groups did not make a significant improvement to the model. However, this analysis did indicats that the mean Tlco level for leavers from the PVC factory who were current smokers was significantly lower (P < 0.1) _than current PVC factory employees who were non-smokers. However, the age slope of this group did not differ significantly from that of current PVC factory employees who were non-smokers. Eenee the modal used was the one in which different intercepts and age slopes were allowed for the three smoking groups. For reasons of consistency the FEVX analysis was also based on this same modal although there was no significant improvement in the amount of variation explained as there had been for the Tlco analysis. The results for FVX analysis show that there was a significant difference (P < 0.1) in the rate f loss of FEVt with age between non-smokers end current smokers who experienced a greater rate of loss of FEVX (Table 2). CMft 00775 APPENDIX J, page 2 TABLE 1 57. Regression for Tlco (ml/min. ma Eg) allowing different intercepts and age slopes for three ""Hwg groups. Variables Age Height Weight Units Tears CD kg Mean 42.2 173.8 80.2 Constant for non-snokers Regression coefficient t -0.2248 0.1552 0.0572 Constants (intercepts) -5.74 4.74 3.23 10.3052 P < 0.001 < 0.001 < 0.002 Effect on intercept of: Current soakers Ex-cookers Effect on age slope for: Current smokers Ex-smokers -2.5288 1.4554 -1.34 0.69 US NS -0.0154 -0.0537 -0.33 -1.08 NS NS . TABLE 2 Regression for FEV^ (C} allowing different intercepts and age slopes for three sookisg groups. Variables Age Height Weight Units Tears cm kg Kean 42.2 174-3 8O.4 Constant for non-soakers Regression coefficient -0.0309 0.0420 ` 0.0003 t -4-55 7.13 0.09 Constants _ (Intereectsl -2*1725 Effect on intercept of: Current ssokers Ex-nokers 0.4209 0.2675 1.24 0.75 Effect on age slope for: Current ssokers Et-saokars - . -0.0149 -0.0096 -1.81 -1.13 P< 0.001 < 0.001 NS NS NS < 0.10 NS CMA 007758 various respiratory symptoms, and gastrointestinal disturbances, such as nausea, vomiting and loss of appetite, are commonly reported by styrene-exposed workers. Other abnormalities reported include headaches, tiredness and sleep disturbance. After a period of exposure, adaptation ay occur and there can be a decrease in the various symp toms . Nevertheless, significant alterations still exist aaong currently employed workers. Several systematic studies of the various clinical ef fects from styrene exposure have been conducted in recent years. Many of these focused on possible neurological alterations and clearly demonstrated adverse findings at moderate styrene exposures (less than most national stand ards). The most extensive of these is.that by investigators from the Institute of Occupational Health of Finland (Seppalainen and Harkonen, 1976; Lindstrom et al, 1976; Harkonen, 1977; Harkonen et al, 1978). They examined 98 workers employed at 24 plants manufacturing FRF products. Air concentrations were sampled and ranged from 5 to 300 ppm. The means of five post-workday urine mandalic acid (MA) concentrations ranged from 7 to 4,700 mg/1 with a lin ear relationship existing between the log of the HA concen tration and the log of the styrene concentration. The mean value of HA in the population was 808 mg/1 and corresponded to an exposure of about 40 ppm of styrene. Abnormal EEG' 6 were found in 30% of those with MA in excess of 700 mg/1, compared to about 10% for those with lower HA values and normal controls (Seppalainen and Harkonen, 1976). Lindstrom et al (1976) noted increased visuomotor inaccuracy (symmetry drawing and Bourdon -Wiersma tests) and lowered psychomotor performance (Hire test) for various MA concentrations rang ing from 800-2,000 mg/1 (See also: Harkonen et al, 1978). Fatigue, irritation, difficulty in concentration, nausea, dizziness, and lightheadedness were more frequently reported by the styrene-exposed workers than by unexposed controls (Harkonen, 1977). A deteriorating EEC among styrena workers has also been described by Klimkova-Oeutschova et al (1973). Alterations of nerve conduction have been documented by Rosen et al (1978) who observed an increased duration and decreased amplitude of sensory action potentials. Lilis et al (1978) suggested the possibility of a decrease in peroneal nerve conduction velocity. The decrease, however, was only asso ciated with length of esiployment and not intensity of expo- CMA 0077A0 sure. Subjective symptoms of physical and mental tiredness after styrene exposure have been reported by Klimkova-Deutschova et al (1973) and Cherry et al (1980), among others. The reported neurological findings among styrene-exposed workers are less serious than those reported in some other groups occupationally exposed to solvents, such as as paint ers (Lindstrom, 1980; Bane et al, 1977). However, the continued exposure to concentrations causing the observed abnorsulities may lead to more serious central nervous system impairment. In addition to neurological disturbances, alterations of pulmonary function have been noted among styrene-exposed workers. Lorimer et al (1977), in an examination of 494 polymerization workers, found a reduction in FEV. to be associated with intensity of exposure and with urine HA concentration. Further, the workers in the higher exposed group reported a greater percentage of acute and recurrent lower respiratory symptoms. Harkonen (1977) reported an increase in incidence of chronic bronchitis which correlated with intensity of exposure. On the other hand, Axelson et al (1978) did not find any abnormalities of pulmonary func tion asiong 27 FRF boat manufacturing workers. Laboratory test results have been rather unremarkable. Lorimer et al (1977) suggested the possibility of increased lymphocytosis among polymerization workers and Checkoway (1982) found a correlation between decreased red blood cell count and increased basophil count with styrene/ butadiene exposure. Increased blood enzyme concentrations, charac teristic of abnormal liver function, occasionally have been reported. Lorimer et al (1977) found a significant increase in concentrations of GGTP (gamma glutamyl transpeptidase) and Hotx (1980), noted increased concentrations of OCT (orinthine carbamoyl transferase) and ALAT (alanine amino transferase) among polymerization workers. SUMMARY OF HOMAN MORTALITY AMD MORBIDITY The limited epidemiological studies of mortality asso ciated with styrene exposure do not demonstrate any excess cancer risk that can be attributed to styrene, although elevated risks for leukemia have been noted in exposed groups. However, these excesses may be related to exposures CMA 7761 to other chemicals, such as ben2ene. The studies are se verely limited because of the relatively low styrene expo sure of the groups studied. They provide no guidance on carcinogenic risk in populations much more heavily exposed as in the FRP industry. The significant clinical findings among styrene-exposed workers are largely limited to abnor malities of the central nervous system, where a variety of objective and subjective symptoms have been reported in the FRF industry. Concern for long-term deguerative neurologi cal disease exists for continued long-term exposure in this industry. The possibility of pulmonary effects from styrene exposure has also been noted. REFERENCES Axelson 0, Gustavson J (1978). Some hygienic and clini cal observations on styrene exposure. Scand J Work Environ Health 4:215-219 (suppl 2). Checkoway H, Williams TM (1982). A hematology survey of workers at a styrene-butadiene synthetic rubber manu facturing plant. Am Ind Hyg Assoc 43:164-169. Cherry N, Waldron HA, Wells GG, Wilkinson RT, Wilson HK, Jones S (1980). An investigation of the acute behavioral effects of styrene on factory workers. Brit J Ind Med 37:234-240. Delzell E, Monson RR (1982). Mortality among rubber workers: VI. Men with potential exposure to acrylonitrile. J Oce Med 24:767-769. Frent2el-Beyme R, Thiess AM, Wieland R (1978). Survey of mortality among employees engaged in the manufacture of styrene and polystyrene at the BASF Ludwigshafen works. Scand J Work Environ Health 4:231-239 (suppl 2). Hane M, Axelson 0, Blume J, Hogstedt C, Sundell L, Tdreborg B (1977). Psychological function changes among house painters. Scand J Work Environ Health 3:91-99. Harkonen H (1977). Relationship of symptoms to occupa tional styrene exposure and to the findings of electroencephalographic and psychological examinations. Xnt Arch Occ Environ Health 40:231-239. Harkonen H, Lindstrom X, Seppalainen AM, Asp S, Hernberg S (1978). Exposure-response relationship between styrene exposure and central nervous functions. Scand J Work Environ Health 4:53-59. Hotx P, Guillemin MP, lob M (1980). Study of some hepa tic effects (induction and toxicity) caused by occupa tional exposure to styrene in the polyester industry. Scand J Work Environ Health 6:206-215. CMA 007762 various respiratory symptoms, and gastrointestinal dis turbances, such as nausea, vomiting and loss of appetite, are commonly reported by styrene-exposed workers. Other abnormalities reported include headaches, tiredness and sleep disturbance. After a period of exposure, adaptation ay occur and there can be a decrease in the various symp toms. Nevertheless, significant alterations still exist among currently employed workers. Several systematic studies of the various clinical ef fects from styrene exposure have been conducted in recent years. Many of these focused on possible neurological alterations and clearly demonstrated adverse findings at moderate styrene exposures (less than most national stand ards). The most extensive of these is.that by investigators from the Institute of Occupational Health of Finland (Seppalainen and Harkonen, 1976; Lindstrom et al, 1976; Harkonen, 1977; Harkonen et al, 1978). They examined 98 workers employed at 24 plants manufacturing FRF products. Air concentrations were sampled and ranged from 5 to 300 ppm. The means of five post-workday urine mandalic acid (MA) concentrations ranged from 7 to 4,700 mg/1 with a lin ear relationship existing between the log of the HA concen tration and the log of the styrene concentration. The mean value of HA in the population was 808 mg/1 and corresponded to an exposure of about 40 ppm of styrene. Abnormal EEG's were found in 30% of those with HA in excess of 700 mg/1, compared to about 10% for those with lower MA values and normal controls (Seppalainen and Harkonen, 1976). Lindstrom et al (1976) noted increased visuomotor inaccuracy (symmetry drawing and Bourdon-Wiersma tests) and lowered psychomotor performance (Hire test) for various MA concentrations rang ing from 800-2,000 mg/1 (See also: Harkonen et al, 1978). Fatigue, irritation, difficulty in concentration, nausea, dizziness, and lightheadedness were more frequently reported by the styrene-exposed workers than by unexposed controls (Harkonen, 1977). A deteriorating EEC among styrene workers has also been described by Klimkova-Deutschova et al (1973). Alterations of nerve conduction have been documented by Rosen et al (1978) who observed an increased duration and decreased amplitude of sensory action potentials. Lilia et al (1978) suggested the possibility of a decrease in peroneal nerve conduction velocity. The decrease, however, was only asso ciated with length of employment and not intensity of expo- CMA 0077&0 Spirt** R, Van Ert M, Gamble J, Wolf P, MeMichael AJ (1976). Toxicologic, industrial hygiene and epidemiologic conside rations in the possible association between SBR manufac turing and neoplasms of lymphatic nd hematopoietic tissues Zn: Proceedings of NlDSH Styrene-Butadiene Briefing. US Department of Health, Education and Welfare Publication (HIOSH) 77-129. Tossavainen A (1978). Styrene use and occupational exposure in the plastics industry. Scand J Work Environ Health 4:7-13 (suppl 2). CMA 007764