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?x?crt ;:c. tm/^2/4 UDC 612.2 : 67?.7^3 AN EPnEyiCLCGICAL STUDY OF THE LUNG FUNCTION CF -CKKZfiS AT A FACTGP.T MANti FACTORING FOLYV^YLCIILGaiDS by HH Lloyd S Gauld L Copland CA Soutar JANUARY 1932 007702 INSTITUTE OF OCCUPATIONAL MEDICINE AN EPIDEMIOLOGICAL STUDY OF THE LUNG FUNCTION OF WORKERS AT A FACTORY MANUFACTURING POLYVINYLCHLORIDE by MI Lloyd, 3 Gaul<1, L Copland, CA Soutar Medical Branch Institute of Cccupatiosal Medicine, Roxburgh Flace, EDINBURGH IKS 9SU. (Tel. 031 667 5131) JANUARY 1962 CMA 007703 (ii) CONTENTS Page No. ABSTRACT 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 The foundry . . . . 2. METHODS..................................................................................... 2.1 Selection of the surrey population ... 2.2 The medical surrey ....... 2.3 Methods of analysis ................................................... 2.3.1 Classification of smoking histories . 2.3*2 Analysis of data from total surrey population ....... 2.3*3 Selection of canes and controls . . 2.3.4 Case-control study ...... (iv) 1 1 2 2 3 3 4 5 6 6 6 7 7 7 8 8 3. RESULTS............................................................................................ 3.1 Description of total surrey population . . 3.2 Analysis of lung function data from total Surrey population ........ 3.2.1 Calculation of predicted raiues and standardised residuals ... 3.2.2 . Distribution of standardised residual raiues of T-co and FEV^ for total surrey population ...... 3.2.3 Selaction of eases and controls . . 3.3 General features of cases, controls and the total surrey population ...... 3.3*1 Age, height and weight .... 3.3*2 Employment status and smoking habit . 3*3.3 Dung function ....... 10 10 10 10 10 10 H 11 11 11 CMA 007704 (lii) Page No. 3.4 3.5- Clinical description of T*-co eases and FEVt eases ......... Case-control study ........ 3.5*1 Occupational histories of cases and controls ........ 3*5*2 Smoking habits of cases and controls . . 12 12 12 14 4. DISCUSSION............................................................................................. 16 5. CONCLUSIONS AND RECOMMENDATIONS................................................... 19 ACKN CWLEDGSMZUTS REFERENCES TABLES FIGURES APPENDICES CMA 007705 Report No. TM/82A Civ) INSTITUTE OF OCCUPATIONAL MEDICINE AN E?ID3\IQLCGICAL STUDY OF THE LUNG FUNCTION OF WORKERS AT A FACTORY MANUFACTURING PCLTVINYLCKLORIDE by MB Lloyd, S Gauld, L Copland, CA Soutar ABSTRACT We have conducted an epidemiological study to investigate a resort that some men working in a factory manufacturing polyvinylchloride (PVC) had abnormally low values of one lung function te3t, namely the single breath transfer factor for carbon mcnoxiae (Tlco). 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 s-posure to possible respiratory hazards at the PVC factory. Each man's Tlco was measured, and smoking history and detailed accusational 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 Tlco of current snd 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 Tlco; and a case-control study. In this, men with the lowest Tlco 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 those with the highest values, -Thw T\.co resurts"*adng this c6mfc~Ined"~population conformed to a Normal distribution after allowing for age, height, weight and smoking habit, snd did not suggest that a substantial number of men had clinically important impairment of their Tlco. The 51 men selected as 'cases' included 15 men whose Tlco was abnormally low (less than 73 of published predieted values), of whom JhhU*" we re PVC workers and were foundrymen. Among the 19 eases working at the PVC factory the pattern of lung function abnormality suggested that the low Tlco was (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 ware slightly over-represented among the eases, 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 eases, and this difference approached statistical significance at conventional levels. There was, furthermore, a statistically significant association between low Tt-co 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 cases included slightly more smokers than the controls, and those cases who smoked, smoked slightly mors heavily than controls. The relative importance of these end other factors in causing the lung functional abnormalities is not clear, but these findings give some support to the hypothesis that work in the FVC 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 ether causative factors would ba desirable, together with a clinical assessment of the lung damage in selected men. CW* 007707 1. INTRODUCTION The health of workers employed in the manufacture of polyvinylchloride (?VG) has teen a cause of concern during recent years. Some adverse effects of exposure to vinyl chloride monomer ('/CM) 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. Vinvl chloride is the basic raw material Tiseu in the production of PVC. Although the manufacturing process was first developed in 1923 in the USA it was not until 3G years later that evidence of the toxic effects of vinyl chloride exposure began to accumulate. GO "dvr. ('c" 5) -./ns the first to describe ecro-osteolysis in reactor cleaners in Belgium and in the following year bUCIU (1967) described Raynaud's phenomenon among workers in a PVC factory. Changes in the skir. and internal ergans were subsequently recognised nd in '9'7t* the tsrrn 'vinyl chloride dinetse' was used to describe the 3yrdrcme which has aar.y features in common with scleroderma (VSLTKAN *t al,, 1975). The hepatic effects of exoosurc to VCM have aroused the most interest and include ncn-callgnant changes. It was the discovery cf the association between vinyl chloride exposure and angiosarcoma of the liver (CREECH and JOHNSON, 197*0 which caused the greatest concern and affirmed the need for stricter control of exposure levels. In 175 regulations were introduced which established a ceiling exposure value of 30 parts per million (ppm) snd an eight-hour time weignted average (TVA) of 10 ppm. In 1930 the permitted maximum exposure was reduced to an annual average of 3 ppm. 1.1 Reaoiracarv effects of VCM and PVC The work descrioed in this report was confined 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 proceas. Previous studies involving the use of animals, observation on patients and epidemiological surveys, have provided information on the potential respiratory effects of these compounds. CMA 007708 2, 1.1.1 Animal 'studies The toxicity of both VC and PVC has bees investigated in anisal experiments. P30DAN et al. (1975) exposed guinea pigs to 1C# vinyl ehloride concentration for two hours daily for periods of up to three sonths. At autopsy the lungs of all txposad animals showad tha presarea of fibrosis which was most severe in tha animals which had had tha longest axpoaura tisa. ACAgVfAL at al. (1978) studied tha affect of intratracheal injections of PVC dust in rats and found that Inflammatory changes wart induced in tha terminal and respiratory alveoli and that granulomatous lesions associated with multinuclasted giant cells developed. Similar giant eell3 and histiocytes ware Identified in the alveoli of the lungs of small mammals which were kept in the bagging area of a PVC factory (TBQNGIA at al.. 197*0. 1.1.2 Clinical studies There have been isolated case reports of pulmonary disease in workers employed in factories manufacturing PVC. ABNADD et al. (1Q"3) studied s 53-year-old man who had worked for 23 years in the bagging plant of a PVC factory. Eis cheat X-ray showed mcronedular shadowing and lung biopsy revealed large nunbers of macrophages containing particulate material and moderate diffuse fibrosis and a few alveolar granulomata. However, his symptoms were few and apart from a slight reduction in. 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 VCH. DARKS (1976) investigated 14 sen who nad been employed in a PVC manufacturing plant exposed to VCH and all of whom complained of breathlessness. He found that thoir chest radiographs were normal. In six of these men transfer factor for eerbon monoxide is reported as being Impaired but no meesurements or details of other lung function tests are given, lung biopsy from one of the men shoved focal alveolar wall thickening end macrophages present in alveolar spaces. LANGE et el. (1973) described some cases ef VC workers with impairment of transfer factor for carton monoxide, but the relationship with occupation was not* clear. CMA 007709 3 1.1.3 Epidemiological studies Studies of pulmonary function of workers employed in PVC manufacturing plants have produced conflicting results, and it has not always been possible to separate the effects of ?VC dust from potential effects of VCM. A high prevalence of abnormal lung function, mainly obstructive in type, was found by KILLEB et al. (1975) and LUIS et el. (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. VEETKIN 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 tests. CHIVEH5 et al. (19^0) similarly found no apparent impairment of lung function among 509 employees in a PVC factory of whom10b were exposed to PVC dust only, 112 to non-chlorinatad solvents only and the remaining 293 ware exposed to a mixture of both. Ho difference between the three groups was identified and the observed impairment of lung function in some men was related entirely to the effects of smoking. However, measured personal exposures ware not available for these men. A study of 8l& men currently and previously employed at a PVC manufacturing plant (SOUTAH rfc al., 190) in which estimates of personal exposure to PVC dust were based on detailed occupational histories and current measurements of dust levels is the factory showed a statistically significant --reduction in tests of lung function among men with the highest PVC dust exposure ,~and-_lome-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 concern about some employees whose lung function, particularly the CMA 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 PTC 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, oceunational and environmental factors. Tho total survey population included the workforce of two factories; one was the ?VC factory of interest and the other was a large iron foundry situated a few hundred yards away. 1.2.1 The P'/C 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 - 197k) emulsion polymer, which has a smaller particle size than suspension polymer, had been manufactured in one of the two 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 presence of other substances acting as catalysts and surfactants, polymerization of TCM 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 tu_ssotjga-siXos or bagged and stared in the warehouse before being"dispatched. The manufacturing .process la operated in batches throughout the 24 hours and the workforce is divided into four shifts. Is the reactor mcA dryer buildings sen usually start as 'S' operators and can then proceed to be 'A* operators and sometimes "Lead' operators. , Available data-suggeat -that prior to 1973 levels of TCM ia fbe factory were considerably higher then the current low levels. Staring the period 1969 - 1979 sea worldlag In the reactor buildings* and particularly those involved, in the manual cleaning of reactors* are likely to have been exposed to the highest levels of VCM. CMA 00771 5 1.2.2 The foundry The foundry was situated near the PVC factory in the aame 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. DMA 007712 6 2. METHODS 2.1 Selection of the survey population All 177 men currently employed at the PVC factory were incited to take part. The names of another 263 men who had worked at the plant since it started production in 19o9 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 canfined 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 Council Questionnaire of Reepiratcry Symptoms (MRC, 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 epent in each of them noted. All PVC factory employees had measurements of forced expiratory volume in * one second (TSVl), forced vital capacity (FVC) and gas transfer factor for earbon monoxide (Tuco). For foundry workers, approval was ootained for measurement only of TVco. Measurements of FEVt and FVC were made using an electronic dry rolling-seal spirometer (Ohio 800). After a practice expiration, three forced expirations which wore considered to be technically satisfactory from a maximum of six wore recorded. The maximum values of FEVt and FVC, not necessarily in the same breath, were used for the analysis, and the ratio of 5ZVX to FVC was derived from thes figures. CM* <>?713 7 Single breath gaa transfer factor for carbon monoxide (T-co) 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 E, P.iC. 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 IQt, 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 teats was used in the analysis. Each man was weighed fully clothed and his standing height measured. 2.3 Methods of analysis The data were 3tudied 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 sad ex-smoker. Mo distinction was made in the analysis between type of smoking and the two 'smoker* groups included smokers cf manufactured cigarettes, hand-rolled cigarettes, pipes and cigars, since the majority of mss smoked manufactured cigarettes. 2.3*2 Analysis of data from total survey population The distributions of lung function and various explanatory variables * A standardised residual, SB, 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 SH " (observed value - value predicted from fitted equation) (estimated standard deviation of the prediction) CMA 007714 t 8 ware examined for systematic patterns amongst current and former employees of the PVC factory and current employees at the foundry. This was further explored for Twco and FSV1 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 SH values. The distribution of S3 values was examined to see if there was evidenc 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. 2.3.3 Selection of esses end controls For each lung function variable those men with the largest negative SR values were ehesen as cases. Two group3 of controls were selected randomly, firstly from those men whose SRs were clustered around zero and secondly from those with the largest positive SRs. 2.3.** Case-control study Cases 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 cases and controls were studied for systematic differences. Fisher's exact test, chi-squared tost for 2x2 contingency tables and chi-squared teat for linear trend were used where appropriate. Classification of smoking and employment histories Smoking histories were classified as they were for the total population (see Section 2.3.T). Additional information about the number of cigarettes smoked and age of starting smoking was analysed in the casecontrol study. Bread occupational categories were defined for both PVC CMA 00771 -- 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 la 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 recognised hasards, 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 hasards could possibly arise although they would be less lively than those of the otner groups (see Appendix 2 for a list of 'other noxious' jobs). Employment of men in ths manufacturing of PVC other than at the PVC factory was also noted. CMrt 007716  10, 3. RESULTS 3.1 Description of total survey population A total of 488 oen was seen consisting of 165 current ?VC factory employees (95& of those who were asked to participate), 102 PVC factory leavers (39 of those who were invited) and 221 foundry employees (786 of those invited). Three oen Cons front each employment category) did not complete the Tlco measurement and one foundryraan did not have height and weight values recorded; the analysis was based on the remaining 484 men. FEVt and FVC measure ments were not obtained from three FVC factory leavers and were not carried out on the 221 foundrynen and the analysis was based therefore on 264 men. 3*2 Analysis cf lung function data from total survey population 3.2*1 Calculation of predicted values and standardised residuals The effects ar age, height, weight and smoking habit on the Tlco and FSVi 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 FEVj 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 ft*co for the total survey population showed a symmetrical distribution, with no greater number of men in the negative tail of th 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 FSVj, SR distribution there were slightly more extreme negative values than extreme positive values (Figures 1 and 2). 3*2.3 Selection of cases and controls It was decided that about 30 cases would form a study group of appropriate size. The threshold S3 value for Tlco below which there was approximat ly this number of men. was - 1.5. giving )1 a n. A CMA 007717 11 control group of 31 men was selected randomly from those men with SS values between - 0.25 and + 0.75 inclusive (Tlco 'average' controls). A second control group of 31 'extra-healthy' sen was selected randomly from those with S3 values in excess of + 0.75 (Tlco 'healthiest' controls). Similarly 30 men with an FE7i SB value of less than - 1.1 were selected as 7SVt cases and two control groups, each of 30 men, were selected randomly from those with an SB value between - 0.25 and + 0.75 inclusive (FEV^ 'average' controls) and from those with an SB value in excess of + 0.75 (3EVt 'healthiest' controls). 3*3 General features of cases, controls and the total survey population 3.3.1 Ave. height and weight The mean age, height and weight of Tmo cases and controls, FF/X cases and controls and the total population are given in Tables 3 and 4. Tlco eases and controls were of similar age but cases tended to be taller than the control groups. Although the mean ages of T<-co cases and control * groups were similar, study of the age distributions (Table 5) showed an excess of current ?VC factory employees in the ^5 - 54 age group when j* compared with both groups of controls and the rest of the population. FEVj^ cases were slightly older and taller than the controls and the rest of the population hat there was no difference in the age distribution between employment groups or cases and controls. 3*3*2 Smoloyment status and smoking habit The employment status of cases, controls and the total population is shown in Tables 6. and 7* PVC factory employees were slightly over represented amongst Tlco cases but this could easily have occurred by chance. Differences in smoking habit are discussed in a later section. 3*3*3 Lung^Uiwtion The mean values of Tlco for Tlco eases end controls and the total population are shewn in Table 3 and mean values of Tlco, FEVt and FVC for FEVt eases and controls are shown in Tabls 4. CMA 007718 12 Observed Tueo and FEV: values were expressed as a percentage of values predicted on the basis of Cotes's regression model (COTIS, 1979) and the distribution of these values for cases, controls and the total population are shown in Tables ? and 9. Clinical description of Tloo cases and FSV, cases Fifteen men (nine FVC workers and six foundryraen) of the 31 Tuco cases had Tuco values below 7C5> of their predicted values and four of these were below 6c (Table S). Nineteen of the 31 cases were from the PVC factory and of those, four man had F2V. values of less than 80s of their predicted value and low FEVl/FVC ratios indicating airflow obstruction. The remaining 15 men had FEV1 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 Tlco standardised residual values are given in Tahle 10. Of the 30 FEVX cases, 15 had observed 7EVt values below 80s of their predicted valuer and 10 of these were less than 70S (Table 9). The majority (10) of the 13 men -with reduced TSVl had FEVl/7VC ratios below 7C% suggesting airflow obstruction. Seven of the F3Vt eases were also selected as Tvco cases.. 7.5 Caae-contrel study The occupational histories and smoking habits of oases and controls were compared in ordor to explore the observed differences in their lung function. 3-5.1 Occupational histories of cases and controls Analyses of the current employment status of cases and controls showed that PVC factory workers were slightly over-represented amongst 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 to show any differences between T-co cases and their 0077*9 13 controls (Table 11), though mere cases 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 PVC workers alone are considered but if the foundrymen are iacludad, 11 of 31 eases (35?0 had worked in category 1 jobs in the PVC factory, whereas only 10 of 62 controls (l6S) had done the same. The difference is significant at the 7& level. These occupational differences were not apparent for the FSV, 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). Pre-IQ7? 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*75 the exposure levels were low. The cumbers or cases and controls who had been employed at the PVC factory before 1st January 1975 were compared. Seventeen of the 19 PVC worker Twco cases had been employed before 1975 compared with five of the 15 'healthiest' controls and 11 of the 13 average controls (Table 1*0. Using a X3 test for trend, there was strong evidence to suggest a significant increase in the proportion of men working before 1975 over 'healthiest' controls, 'average* controls end cases. Looking at comparisons between groups only the difference between cases and 'healthiest' controls was significant. Analysis of the duration of employment of men within different age groups showsd that pre-lQ75 working was seen in younger as well as in older men (Tables 15, 16, 17). No differences were seen in the number of men employed before 1975 between PVC factory FE7t 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 Tueo. CMA 007720 14 .Exposure to emulsion oolyraer The employment of cases 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 thesa who had not been exposed to either* Similar proportions of Tlco cases and controls (Table 20) and FEVt eases and controls (Table 21) are represented in each lof these three groups. There is no evidence that exposure to emulsion polymer adversely affected the lung function of those who worked with it. Previous employment in other industries There was no evidence that the observed differences between cases 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 thorn working in other industries which might be considered noxious \..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 Twco cases (&%) were current eigarette smokers than were either group of controls (4S) or total survey population (48&) (Table 27). This difference was not seen between the PEV^ cases and controls but there were more ex-smokers among the PSVj cases than there were among the controls (Table 26). The enoklag histories were examined, in greater detail by analysing the number of cigarettes which current eigarette smokers smoked daily both on weekdays and during the weekendt the number smoked by each man during the maximum smoking period of his life and the age at whieb each man started smoking. There was no significant difference in the number of cigarettes smoked on weekdays between both groups of eases and the'healthiest' controls (see Figures 3 and 4), and similar results were found for 'average* controls. CMA 007721 -- 15Analysis o*" weekend smoking showed that more Tlco cases smoked 25 or more cigarettes per day than did the Tlco healthiest controls (Figure 5). No such difference was found to exist with average controls. Comparing the weekend smoking habits of PVC factory and foundry Tlco cases, it was found that a larger proportion of foundrymea smoked mere than 25 cigarettes per day (Figure 5). For the FS,/l 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 man at the PVC factory, five of the 13 Tlco coses, 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 orison by chance. The age at which men started smoking was also examined* Thers were significant differences between cas3 and controls. Cf the 20 Tueo cases who were current smokers, eirnt had started smoking by the 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 14 'healthiest' controls (Finure ?a), while the figures for average controls were that six out of 15 had started smoking by ths age of 16 (Figure ?b). Of the 13 FEVt cases who wsre current smokers, seven had started smoking by the age of 16 compared with two of the 11 'healthiest' controls (Figure a). These differences were not seen between cases and 'average' controls (Figurs 9bJ. In conclusion Tlco easts and 'healthiest' controls and FEVt 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 eaaes at the PVC factory and the foundry. In general, cases started amoking at a younger age than controls. CMA 007722 .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 to possible respiratory hazards at the PVC factory, but who were exposed to similar environmental conditions outside their workplace. In all 265 men from the PVC factory and 219 sen from the foundry were included in the Tlco analysis. The Tlco residuals among this combined population conformed approximately to a Normal distribution after allowing for age, height, weight and smoking Uiabit, and did not suggest an undue excess of extremely low values. This kndicated that it was unlikely that a substantial number of men in the '^hole population were suffering from * clinically important reduction of the Tlco. In the case-control study the 31 men with the lowest TLeo sfter allowing for age, height, weight and smoking habit were selected as 'cases'. This does not imply that all 51 were suffering from lung disease, but among them were 15 men whose Tlco was less than 7<36 of the value predicted by published normal values, s level which would generally be regarded as abnormally low. Among the 19 cases at the PVC factory the pattern of lung function accompanying the low Tlco was that of definite airflow obstruction in four menT and possible airflow obstruction in another seven man, suggesting the presence of emphysema. The remaining eight men did not have evidence of airflow obstruction or reduction of their lung capacity (ital capacity). This pattern is unusual in clinical practice, and may posaibly reflect pulmonary fibrosis or disturbances of the blood flow in the lungs. The degree of reduction of transfer factor of carbon monoxide and aaaoeiated airflow obstruction might have been sufficient to cause breathlessness on exertion in some of these men* 007723 CHft 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 ('average1 and 'healthiest' controls). The reasons for 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 ware least likely to have been affected by noxious influences, but also cculd conceivably include men who were highly resistant to these influences, and would therefore not be suitable for the comparisons ms.de in this study. The PVC workers were slightly over-represented among ths casss with low Tlco, though chis 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 VCM was most likely to have occurred in the past, wars also slightly over-represented among the cases, and this difference approached statistical significance at conventional levels. Thsre was, furthsrmore, an association between low gas transfer factor and a history of having worked at the PVC factory before 1975* This dats 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 btfora 1975 was not found among foundry workers. This conjunction of findings suggests that an unknown environmental or 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 007724 18. 3 been much' higher than post-1975 levels. Some support for this is provided by published case reports of VCK .workers with impairment of gas transfer factor, but proof of association has been lacking ies.t expo5ur83_wottid-JiSTgre though it is possible that many workers throughout the factory were exposed to a lesser degree. It is also possible that exposure to respirable PVC dust may have contributed to the low gas transfer factors, for this dust has been shown in other studies to he associated with impairment of other aspects of lung function (though not the gas trarsfer factor) and slight cnest radiographic abnormalities (KASTfcANGELO et al., SOTTAS et al., 1980). O There was no evidence to suggest that a current risk to respiratory Its health exists at either the PVC factory or foundry. ^kSome differences m smoking habit were found between cases and controls ildnon-smokers being slightly commoner among controls, and heavier smokers fijslightly commoner among the eases. The eases 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 tka reductions of gas transfer factor in the eases, 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 thosa man who had left the PVC factory was low (35K) If the men not examined had includad either ar. excess or deficiency of men with impaired gas transfer factor compared with the population examined', then the analysis of the distribution of values smong the population seen could be unrepresentative to that extent. A similar analysis f*or another lung function test, forced expired velum 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 SLCCHKSNDATTCNS We found no evidence of an unexpectedly large number of men with impairment of their lunm gas transfer factor among either PVC factory or foundry employees. There was, however, a small number of men in both factories with impairment of their transfer factor. This could not be shown 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 history 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 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. 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, tog*ther with a clinical assessment of the extent of lung damage in selected men. CM6 007726 ACKNOWLEDGEMENTS This study was carriad out with tha full co-oparatiou of tha management and workforce of Vinatax Ltd., to whoa we are grateful for financial support* We also thank the management and workforce of tha foundry for their generous co-operation in the study. 21 REFERENCES AGARWAL OK, 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. ARNAI/D A, POMMIES de SANTI P, GARBS L, PAYAN H, CHARPIN J (1978) Polyvinyl chloride pneumoconiosis. Thorax; 33* 19 - 25. CHIVEHS CP, LAtfRENCE-JONES C, PADDLE GM (1<?30) Lung function in workers exposed to polyvinyl chloride dust. British Journal of Industrial Medicine; 37: 147 - 151. COPDIER JM, FIEVE2 C, LEFSVRS M-T, S2VRIN A (19663 Acroostcolyse et lesions cutanees assecieeo ches deux ouvriers affectees au nettoyage d'autoclaves. Cahiers de Kedecine du Travail; 4: 14 - 19. COTES JE (1979) Lung function. Oxford: Scientific Publications: 389 - 385. Blackwell CREECH JL, JOHNSON HN (1974) Angiosarcoma of liver in the manufacture of polyvinyl chloride. Journal of Occupational Madicine; 16: 150 - 151. DARKS CS (1978) Vinyl chloride and the production of PVC (Discussion). Proceedings of Royal Society of Medicine; 69* 280. FRONGIA N, SPINAZZCLA A, BOCARELLI A (1974) Lesioni polmcnari sperimentali da inalaxione prolungata dl PVC in ambiente di lavoro. Medicina del Lavoro; 87: 321 - 342. GAMBLE J, LID S, HcMXCHAEL AJ, VAXWEILER RJ (1978) Effect of occupational and nonoceupational factors on the respiratory system of vinyl chloride and other workers. Journal of Occupational Medicine; 18: 859 " 870. HIGGINS ITT (1970) Occupational Factors in Chronic Bronchitis and Emphysema. Review. In: Orie NGM, Van Der Lend* R, eds. Bronchitis III. Proceedings of the Third International Symposium on Bronchitis at Groningen, The Netherlands. Springfield (HI.): Charles C. Thomas, 1970: 83 - 99* CMA 007728 22 LANGE CE, jtfHE S, STEIN G, VELTMAH G (197?) Die sogenannte Vinylchlorid-Krankheit - eine berufshedir.a'te Systemsklerose? International Archives of Occupational Health; 32: 1 - 32. LILIS R, ANDERSON H, NICHOLSON WJ, DADM S, FISCHBEIN AS, SELIKQFF IJ (1975) Prevalence of disease among vinylchloride and polyvinyl chloride workers. Annals of New York Academy of Science; 246: 22 - 4l. LILIS R, ANDERSON H, MILLEH A, SSLIKOFT IJ (1976) Pulmonary changes among vinyl chloride polymerisation workers. Chest; 69: (Suppl. 2 Feb.), 299 - 503. MASTHANGELO G. MAMNC M, MARCER G, BAIM'CLUCCI GO, GEMIGNANI C, SALADINO G, SIMONATO L, SAIA 3 (1979) Polyvinyl chloride pneumoconiosis: epidemiological study of exposed workers. Journal of Occupational Medicine; 21: 5**0 - 5^2. MEADS 7, SAUNDERS MJ, HYETT F, REYNOLDS JA, PEARL N, COTES JE (1965) Automatic measurement of lung function. Lancet; 2: 573 - 575. MRC (1976) Medical Research Council Working Pa-ty on Research into Chronic Bronchitis. Publications Group, Medical Research Council, 20 Park Crescent, London WIN 4al. MULSH A, TEIRSTEIN AS, CHUANG H, SELIKOFF IJ (1975) Changes in pulmonary function in workers expoaed to vinyl chloride and polyvinyl ehloride. Annals of New York Academy of Science; 245: 42 -- 52. P80DAN L, SUCIU I, PISLARU V, ILEA E, PA30U L (1975) Experimental chronic poisoning with vinyl ehloride (monochloroethane). Annals of New York Academy of Science; 246: 159 - 163. SOUTAR CA, COPLAND LH, THORNLEY PE, HURLEY J7, OTTERY J, ADAMS WGF, BENNETT B (i960) Epidemiological study of respiratory disease in workers exposed to polyvinylchloride dust. Thorax; 35: 644 - 652- SICIU X, DREJMAN I, VELASXAI M (1967) Study of disease caused hy vinyl chloride. Medicina del Lavoro; 58: 261 - 271. CMA 007729 23 VELTMAN G, LANGS CE, JtfHE S', STEIN G, BACHNE8 tj (1975) Clinical aanifestations and course of vinyl chloride disease. Annals of New York Academy of Science; 246: 6 - 17. VE3TKIN YI, MAMONTOV YR (1970) Tbe state of the bronchi and lungs in workers employed in the manufacture of polyvinyl chloride articles. Gigiena Truda i Professional * nye Zabolevaniya; 14: 29 - 32* CMrt 007730 TABLE- 1 25 Classification of all jobs at Vinatex into six broad occupational groups. Broad occupational group Jobs included in group 1 All men working in reactors 1 and 2 * 2 Dryer room 3 operators * 3 Dryer room Lead, A and A/3 operators 4 Warehousemen, saintenanee staff, laboratory staff and drivers '** 5 General staff who visit plant, e.g. shift supervisors and foremen 6 Ifanagcment and office staff These men art moi"t likely to have been exposed to high concentrations of VCM in the cast. 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 26 TABLE 2 Classification of foundry jobs into seven broad occupational groups. Occupational ."roup No. Description Jobs included in group 1 Furnace and malt: furnace operator, burnsr, charger, weirher, skimmer, smelter, slarman, ladle repairer, concrete linar. 2 Sand and blasting: coremaker, sand tester, sand mixer, shot blaster, core stripper, knock-out, brick oaker. 3 Metalwork: driller, grinder, blacksmith, tinsmith, wagon repairer, rope splicer, cucola repairer, maintenance fitter's mate, maintenance fitter, turner, trainee in the training centre, borer, saw renairer, wagon rooairer, milling operator, inspector in machine shop, welder. 4 General and other: labourer, patternmaker, plater, platelayer, pipe loader, crane driver, driver, eleanor. technician, trainee, pine roller, slinger, quality control, joiner, greaser, inspector, saddler, bricklayer, core inspector, desrateher, hydraulic attendant, shunter, plumber, oipe recorder, runner operator, sawyer, staff, power house attendant, canteen, tool room attendant, electrician, storeman, ore crusher, ram driver, safety officer. 3 Paint and dipping: dipper, paint sprayer, painter and decorator. 6 Casting: caster, manhole maker, socket man, machine moulder.. 7 Pettier: fettler -- TA2LE 3. 27. Features of Tixo cases, controls and total surrey population. Mean (and standard deviations) of age, height, weight and Tlco. Sumter of sen Cases 31 Tlco Groups Controls Controls (average) (healthiest) 31 31 Total survey population 484 Age (y=e) Mean 41.8 (SD) (10.2) 42.3 (12.5) 40.3 (11.3) 42.2 (11.9) Height (css) Mean 176.1 (SD) (7.D 174.0 (6.6) 173.9 (5.6) 173.8 (7.0) Weight (l=Ss) Mean 32.7 (SD) (13.3) 34.9 (13.5) 79.2 (9-5) 30.2 (12.6) Tlco (ml/sin. ms Eg) Mean (SD) i 22.2 (4.D 31.8 (2.9) 37.3 (4.3) 30.5 (5.9) CHA 007733 __ TA3LE 4 28. Features of FE7t eases, controls and total survey population. Mean (and standard deviations) of age, height, weight, Ttco, FE7t and FVC. Number of men Cases 30 Tlco Groups Controls Controls (average) (healthiest) 30 30 Total survey population 264 ige (yrs) Mean (3D) 43*3 (11.0) 41.3 (12.5) Height (ess) Mean (SB) 1?6.0 (7.4) 174-5 (6.6) height (kgs) Mean (SD) 82.2 (13.3) 78.4 (10.1) FEVj (litres) Mean (SD) 2.7 (0.7) 3.9 (C.7) FTC (litres) Mean (SD) 4.1 (0.9) 5.1 (0.8) Tuco Mean (ml/mln. maiffg) (SD) 29.1* (6.8)* 32.3 (6.0) 42.1 (12.0) 175.9 (8.0) 30.4 (11.5) 4.5 (0.8) 5.9 (0.9) 31.3 (6.5) 42.2 (11.8) 174.3 (7.1) S0.4 (12.3) 3.7 (0.9) 4.9 (1.0) 30.5** (6.1)** * Value based on 29 observations* ** Value based on 262 observations. 007734 CM* TABLE 5 Age distribution of Tuo esses and controls and the total survey population by employment status. CASES PVC current men PVC leavers Poundrymen AVEHAGE CONTROLS PVC current men PVC leavers Foundrymen HEALTHIEST CONTROLS PVC currant men PVC leavers Poundrymen TOTAL POPULATION PVC current men P/C leavers Poundrymen 0-24 Age ranges in years 25-34 35 - 44 45 - 54 55 - 64 65+ Total 1 46 11 222 1 1 8 1 434 12 141 3 1 12 3 2544 9 4 Ifl 2 3241 12 1 2643 12 3 16 9 37 57 35 26 0 164 4 24 33 19 11 10 101 1? 43 50 /iO 44 0 219 TABLE 6 30 Employment status of Tlco cases, controls and total survey population. Number of men in each employment group with percentages' in brackets. Four men excluded, see text. PVC Current Workers Total surrey population i64 PVC Leavers 101 Foundry 219 Total 484 Cases Controls (average) Controls (healthiest) All ii < 3*0 8 ( 53) 12 ( 26) 9 ( 28) 4 ( 27) 18 ( 39) 12 ( 33) 3 ( 20) 16 ( 35) 32 (ICO) 15 (100) 46 (100) 31 31 31 93 TABLE 7 Employment status of FEVt eases, controls and total surrey population. Number of men in each employment 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 Cases Controls (average) Controls (healthiest) All 14 ( 26) 18 C 3*0 21 ( 40) 53 (100) 16 ( 43) 12 ( 32) 9 ( 2*0 37 (100) Total 264 30 30 30 90 CMA 007736 TABLE 8 Distribution of observed Ttco an a percentage of predicted Tlco using Cotes'a regression odel for noiv-eaokers* Huabers of men (percentages in brackets) for the oases, two control groups and total survey population. ON. NO 1 o NO CMA 0 0 7 7 3 7 Oases Controls (average) Controls (healthiest) Total survey population 50-59 Tlco % -predicted Total 70 - 79 80-8? 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 (45.2) 31 4 (0,8) 14 (2.9) 29 (6.0) 75 114 05.5) (23.6) 120 (24.8) 82 (16.9) 46 484 (9.5) Tflftfie 9 Distribution of observed FEV, aa a percentage or predicted PSV. using Coteu'u regression Model for non-anokera, Dunbars of non (percantagoa in brackets) for the cases, two control groups and total survey population. *9 FVt % prodicted 50-59 60-69 70 - 79 80 - fly 90 - 99 100 - 109 110 - 119 ^ 120 Casey 1 (3.3) H (13.3) 5 (16.7) 3 14 (10.0) (46.7) 3 (10.0) Controls (average) 3 (10.0) 17 (56.7) 9 (30.0) 1 (3.3) Controls (healthiest) 1 (3.3) 6 23 (20.0) (76.7) Total survey population 1 (O.Vi ( 1.5) 6 (2.3) 9 (3.4) 29 (11.0) 48 74 08.2) (28.0) __________ _______ 47 46 (17.8) (17.4) 30 30 30 264 CMA 0 0 7 7 3 8 TABU 1 Details of the tO PVC factory Ttco caaaa Mi th tha Iowaat standardised residual values of Tt-ca. Casa No. 1 did aot complete tha eplrooetrj taat. Predicted values are for aon-eaokara (Cotea, 1979), No. Ago Sttoking oatMory t JO - 3* 0 SB - 2.89 Ttco (observed) 2Q.1 Tt-co "Nco )i FEfj litres EEVt litres fE53 ' 'PVC (oredlctad) cradle tad (observed) (predicted) predicted litres 36.6 *58.3 - - -- 2 65 - 69 I - 2.75 1*.1 27.6 51.3 2.1 3.0 69.8 3.8 3 35-39 c - 2.22 20.1 31.6 63.3 3.6 3.8 95.2 5.2 *1 60,66 E - 2.15 20.9 3 55-39 0 - 2.11 20.8 30.5 32.1 68.6 66.6 1.2 3.2 3.5 36.3 3.5 3.8 86.9 6.1 6 55-59 0 - 2.02 16.7 23.9 61.6 2.6 2.7 95.5 3.3 7 50-5*1 a - 2.01 15.6 25.9 59.5 2.7 3.0 90.6 6.3 8 35-39 ' c - 1.99 23.3 35.5 65.6 6.2 6.1 101.7 5.7 9 *5 - 69 N - 1.92 22.5 29.2 77.0 6.1 3,6 120,1 5.1 10 50-5* c - 1.86 18.6 29.0 66.8 3.6 3.3' 107.9 6.7 - 55.2 68.9 35.1 77.9 77.9 62.2 76.3 8o.o 75.8 Tha abbreviations of aaoWing categorlaa arc aa follovai C currant Booktar E - Er-Booker Tlco unit* aro al/aln. oo Hg. il r life-tong non-oooker cHA 007739 TA3L3 11 PVC factory Tlco cases and controls. Mean 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 wasa 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 EEALTHT2ST CONTROLS Current men Leavers 12 3 1 3.7 (6) 1.6 (5) 9.1 (3) 0.7 CD 3.3 (5) 1.5 O) . Occupational groups 2 34 5 0.4 6.1 9.0 9.7 (5) (3) (4) (2) 0.8 11.8 (6) (1) - - 1.1 6.8 7.1 12.3 (3) (1) (4) CD 0.4 (4) - 1.8 CD - 1.2 10.8 7.3 3.3 (8) (1) (2) C2) 0.5 (3) - - - CMA 007740 TABLE 12 35 Foundry Tuco oases and controls. Mean times (years) spent in each occupational group with number of men in brackets. See Tahle 2 for key to occupational groups. Nunber of men 1 Occupational groups 2345 67 CASES 12 7.3 3.0 12.3 4.0 3.2 11.4 1.0 w (2) (5) (7) (2) (2) (1) AVERAGE C0ST20LS IS 4.6 16.1 30.4 (3) (5) (1) 9.4 (9) . 7.4 (1) 10.6 (5) 2.5 CD healthiest COOTEOLS IS 13.4 (5) 4.5 (3) 12.7 (3) - 12.5 (8) 11.6. m (6) TABLE 13 PVC factory FEVX cases and controls. Mean times (years) spent in each occupational group with number of men in brackets. See Tahle 1 for key to occupational groups. . Hhaher of men 1 Occupational groups 2 34 5 CASES Current men Leavers 14 5*5 1.3 4.3 6.1 6.8 07) (8) (23 (6) (2) 16 2.1 0.8 4.7 1.0 (8) (9) (3) - (2) AVERAGE CONTROLS Current men Leavers 18 3.2 1.2 (10) (10) 12 1.3 0.9 . (5) (7) HEALTHIEST CCETHOIS Current men Leavers 21 9 6.4 CIO) 1.2 (2) 1.2 (10) 0.3 (6) 5.2 CD 4.1 (3) 0.7 (2) - 7.6 7.7 (5) (2) - 1.2 - (3) 7.2 3.6 (9) (3) 2i1 (2) - 6 3.8 (D - 5-0 (2) 3.1 (2) IN o o 2.6 (2) - CMA TABLE 14 For Tuco analysis, the distribution of numbers of PVC cases and controls who had worked at the ?VC factory before 1975 and only after 1975* Pre 1975 Post 1975 Total Cases 17 2 Average Healthiest Controls Controls 11 5 2 10 Total 33 14 i_JL_ 13 15 47 TABLE 15 PVC factory Tt-C0 cases. Number of men within each age group and duration of pre-1975 employment category. Tima of Duration of Age (yrs) employment employment 0 - 24 25 - 34 35-44 Pre 1975 Post 1975 < 2 yr 2 - 4 jr > 4 yr -1 1 1 * 34 2 4 1 Total 1 268 * VJI 1 Total 55 - 64 65 + 19 3 15 2 1 1 19 CMA 00774 37 TABLE 16 PVC factory Tlco average controls. Number of men within each age group and duration of pre-1975 employment category. Time of employment Duration of employment 0-24 25-34 Age (yrs) 35-44 45 - 54 55 - 64 65 Total Pre 1975 Post 1975 Total < 2 yr 2 - 4 yr > 4 yr - 112 21 1 12 11 2533 4 3 4 2 13 TABLE 17 PVC factory TLco healthiest controls. Number of men within each age group and duration of pre-1975 employment category. Time of Duration of Age (yrs) nployment eaployment 0-24 25 - 34 35-44 < 2 yr 1 1 Pre 1975 2 - 4 yr 1 > 4 yr a 1 Post 1975 - 2323 Total 3 524 vn 1 ___ Total 55 - 64 55 * 2 4 * 1 10 1 15 CMA 007743 38 TABLE 18 For FEVl 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 Tlco analysis, the distribution of cumbers of foundry cases 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 007744 TABLE 20 39 For Tcco analysis, the distribution of PVC factory oasas and controls who had worked with different polymers. Cases Average Controls Healthiest Controls Total Bhulsion and suspension Suspension only Neither suspension nor emulsion 6 9 4 8 4 18 3 11 23 2 06 Total 19 13 IS 47 TABLE 21 For FE\\ analysis, the distribution of PVC factory cases and controls who had worked with different polymers. Anlsion 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 PVG. factory Tteo cases and controls. Number of man who have worked in noxious occupations with aean number of years spent by these men in brackets. See Appendix 2 for list of 'other' noxious occupations. CASES Number of men 13 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 - 2 (17.4) Other 8 (11.5) 7 (10.4) 8 \ 1 41/ TABLE 23 PVC factory FEV. cases and controls. Number of men who have worked in noxious occupations with mean rusher of years spent by these men in brackets. See Appendix 2 for list of 'other1 noxious occupations. r.asBK Number of men 30 Steel Noxious occupations Chemicals Coal 10 (4*6) 5 (4.0) 16 (15.7) Other 16 (13.2) AVERAGE. 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 41 Foundry Two cases and controls. Number of men who hav worked In noxious occupations with mean number 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) 1 AVERAGE CONTROLS 13 2 (9.6) 0 (0.0) o a (10.9) - HEALTHIEST CONTROLS 16 2 (4-7) 0 (0.0) 5 (2.9) 5 (7-2) CMA 00774? T4BL2 25 Smoking habits of Tlco easts, controls and total survey population. dumber of men in each making category vith percentages in brackets. NonSmoker Current Smoker Ex-Smcker 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 TA3T.5 26 Smoking habits of ?E7`1 eases, controls and total survey papulation. Number 01 men in each wanking 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) Ks-Smoker Total 12 (40.0) 3C 8 (26.7) 30 9 (30.0) 30 80 (30.3) 264 CMA 007748 ^3. CMA 007749 45. Fig. 3 Number of cigarettes smoked or weekdays by FEV. cases and 'healthiest' controls who are1 current smokers. PVC factory and the foundry, who are current smokers. CMA 007750 J V?. 0 PVC factory Foundry -P*r*--l------- -------- r 10 20 30 40 50 + Wk 1- u 2 3 4 5 6 7 Casa3 No. of cigs. 'Healthiest' controls Fig. 5 Number of cigarettes smoked per day at weekends by Ttco cases and 'healthiest' controls, at the PVC factory and the foundry, who are current CMft 007751 fc9. Fig. 6 Maximum number of cigarettes regularly smoked per day by Tlco cases and 'healthiest* controls, at the PVC factory and the foundry, who are current smokers. Fig. 7 Maximum number of cigarettes regularly smoked per day by FEV^ cases and 'healthiest' controls. CMA 007752 Number of men 51 (a) (b) Number of men Number of men Fig. 8 a) Age when started smoking cigarettes, for T<.co cases and 'healthiest' controls at the PVC factory and the foundry, who are current smokers. b) Age when started smoking cigarettes, for l\co cases and 'average' controls, who are current smokers. (a) (b) 2 PVC factory I < MIS S17 1819 20 2X> 1 * 1m** 234- Age(yi-s) S 0 < 14 516 171813 2D 21 * ______ jo ww'Healthiest' 3 I controls 2 3 4^ n Cases Age(yrs) 'Average' controls Fig. 9 a) Age when started smoking cigarettes, for FEY. 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 APPENDIX 1 SMOKING CPSSTIONMA1FB Do you amoks? If NO la Have you aver 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 parts of question 1, emit remaining questions on smoking. How old were you when you started smoking regularly? How old are you now7 Do (did) you smoke manufactured cigarettes? If YES 4a How many do (did) you usually smoke per day on weekdays? 4b How many do (did) you usually smoke per day at weekends? 4c What was the greatest number of cigarettes you ever 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 sacking 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? Do (did) you smoke hand-rolled cigarettes? If YES 5* How orach tobacco do (did) you usually smoke per week in this way? CMrt 00775A APPENDIX 1, page 2 51*. Do (did) you smoke a pipe? If YES 6a How ouch pipe tobacco do (did) you usually smoke per week? Do (did) you smoke small cigars? If YES 7a How many of these do (did) you usually smoke per week? Do (did) you smoke other cigars? If YES 3a How many of these do (did) you usually smoke per week? For ex-smokers: When did you last give up smoking? 55. APPENDIX Z NOXIOUS OCCUPATIONS la the classification of noxious occupations tha following jobs were included in the category 'other'. Although it is recognised that son# of the jobs included in this category are not widely recognized as 'noxious', it was considered that they may on occasions be associated with health hazards and should therefore be included in the classification of noxious occupations Brewing . Baker Flour miller Farm worker Wocd eutter/sawmill worker Construction worker Bricklayer Plasterer Quarryman Paper mill worker Electrician Joiner Glassvorteer - Welder Scrap burner Foreman Coking plant worker Furnace operator Car body reoairer Paint sprayer Painter/decorator Tarmacadam exposed workers CMA 007756 APPENDIX 3 Development 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 Tlco and age, height and weight and between FET^ 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 Tuco 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 and weight had been taken into account than non-smokers and the age slopes were similar. The model used for Tuco (but not the FEVt 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 TLeo was significantly higher than that of current smokers (P < 0.05) but 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 indicate that the mean Tlco level for leavers from the PVC rectory who were current smokers was significantly low r (P < 0.1) .than current PVC factory employees who were non-smokers. However, the age slope of this group did sot differ significantly from that of current PVC factory employees who were non-smokers. Hence the model used was the one in which different intercepts end age slop s were allowed for the three smoking groups. For reasons of consistency the FEVl analysis was slso based on this same model although there was no significant improvement in the amount of variation explained as there had been for the TLeo analysis. The results for FEVt analysis show that there was s significant difference (P < 0.1) in the rate of loss of FHVt with age between non-smokers and current amokers who experienced a greater rate of loss of TSVX (Table 2). CMA 007757 APPENDIX 3, page Z TA3LE' I 57. Regression for Tlco (ml/min. mm Eg) allowing different intercept3 and age slopes for three nHng groups. Variables Age Height Weight Units Tears cm kg Mean 42.2 173.8 80.2 Constant for son-smokers Regression coefficient -0.2248 0.1552 0.0572 Constants (intercepts) 10.3052 t -5.74 4.74 3.23 P < 0.001 < 0.001 < 0.002 Effect on intercept of: Current smokers Er-smokers Effect on age slope fort Current smokers Ex-smokers -2.5288 1.4554 -1.34 0.89 NS NS -0.0154 -0.0537 -0.33 -1.08 NS NS . TABLE 2 Regression for PEVX (g) allowing different intercepts and age slopes for three smoking groups. Variables Age Height Weight Units Tears cm kg Uean 42.2 174-3 8O.4 Constant for non-smokers Effect on intercept oft Current smokers Ex-mnoker* Effect on age slope fort Current ssokess Ex-smokers * Regression coefficient -0.0309 0.0420 ' 0.0003 Constants (intercepts) -2.1725 t -4.55 7.13 0.09 P* < 0.001 < 0.001 as 0.4209 0.2675 1.24 0.75 NS NS , -0.0149 -0.0096 -1.81 -1.13 < 0.10 NS CMA 007758 CMA 007759 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 (Seppallinen and Harkonen, 1976; Lindstrom et al, 1976; Harkonen, 1977; Harkonen et al, 1978). They examined 98 workers employed at 24 plants manufacturing FRP 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 MA concen tration and the log of the styrene concentration. The mean value of MA in the population was 808 mg/1 and corresponded to an exposure of about 40 ppm of styrene. Abnormal EEC's were found in 30% of those with MA 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 psycbomotor performance (Mira 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, dizxiness, and lightheadedness were more frequently reported by the styrene-exposed workers than by unexposed controls (Harkonen, 1977). A deteriorating EEG 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 sction 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 employment and not Intensity of expo- CM* 007760 sure. Subjective symptoms of physicel and mental tiredness after styrene exposure have been reported by Zlinkova-Deutschova et al (1973) and Cherry et al (1980), aaong others. The reported neurological findings aaong styrene-exposed workers are less serious than those reported in soae 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 abnormalities nay lead to sore serious central nervous systeai impairment. In addition to neurological disturbances, alterations of pulmonary function have been noted aaong styrene-exposed workers. Lorlaer 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 MA 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 aaong 27 FRF boat manufacturing workers. Laboratory test results have been rather unremarkable. Lorimer et el (1977) suggested the possibility of increased lymphocytosis among polymerization workers and Cbcckoway (1982) found a correlation between decreased red blood cell count and increased basophil count with styrene/ butadiene exposure. Increased blood1 enzyme concentrstions, charac teristic of abnormal liver function, occasionally have been reported. Lorimer et al (1977) found a significant increase in concentrstions of GGTP (gamma glutamyl trsnspcptidase) and Hetx (1980), noted increased concentrstions of OCT (orinthine carbamoyl transferase) and ALAT (alanine amino transferase) among polymerization workers. SOfttXT OF BOHAN MORTALITY AND 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 msy be related to exposures CM* 007761 to other chemicals, such as benzene. 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 IRP 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 FRP industry. Concern for long-term degnerative 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 TH (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. Del2ell E, Monson RR (1982). Mortality among rubber workers: VI. Men with potential exposure to acrylonitrile. J Occ 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. HarkSnen H (1977). Relationship of symptoms to occupa tional styrene exposure and to the findings of eleetroencephalographic and psychological examinations. Int Arch Occ Environ Health 40:231-239. HSrkonen 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. Hotz P, Guillenin 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 Huff JE (1983). National toxicology program and carci nogen bioassays of the United States. This volume. IARC (1979). Evaluation of the carcinogenic risk of chemi cals to humans; some; monomers, plastics and synthetic elastomers, and acrolein. Vol 19. Elimkova-Deutschova E, Jandova D, Salamanova Z, Scbwartzova K, Titman 0 (1973). Recent advances concerning the clini cal picture of professional styrene exposure. Cs Neurol 36:20-25. Lilis R, Lorimer WV, Diamond S, Selikoff IJ (1978). Neuro toxicity of styrene in production and polymerization workers. Environ Resh 15:133-138. Lindstrom E, Harkonen H, Hernberg S (1976). Disturbances in psychological functions of workers occupationally exposed to styrene. Scand J Work Environ Health 3:129-139 Lindstrom K (1980). Changes in psychological performances of solvent-poisoned and solvent-exposed workers. Am J Ind Med 1:69-84. Lorimer W, Lilis R, Nicholson VJ, Anderson H, Fischbein A, Daum S, Rom W, Rice C, Selikoff IJ (1976). Clinical studies of styrene workers: Initial findings. Environ Health Persp 17:171-181. McMiehsel AJ, Spirtas R, Gamble JF, Tousey PM (1976). Mor tality earning rubber workers: Relationship to specific jobs. J Oce Med 18:178-185. Reinhardt TJ, Young RJ, Hartle RV (1978). Epidemiologic investigations of styrene-butadiene rubber production and reinforced plastics production. Scand J Work Environ Health 4:240-246 (suppl 2). Monaon RR, Fine D (1978). Cancer mortality and morbidity among rubber workers. J Natl Cancer Inst 61:1047-1053. Nicholson WJ, Selikoff IJ, Seidman H (1978). Mortality experience of styrene-polystyrene polymerization workers. Scand J Work Environ Health 4:247-252 (suppl 2). O'lerg MT (1980). Epidemiologic study of workers exposed to acrylonitrile. J Occ Med 22:245-252. Ott MG, Kolessr RC, Schamweber HC, Schneider EJ, Venable JR (i960). A mortality survey of employees engaged in the development or manufacture of styrene-based products. J Oce Med 22:445-460. Rosen I, Haeger-Aronsen B, RehnstrSm S, Welinder H (1978). Neurophysiological observations after chronic styrene ).exposurd. Scand J Work Environ Health 4:184-194 (suppl 2 Seppaliinen AM, HarkSnen H (1976). Neurophysiological findings among workers occupationally exposed to styrene. Scand J Work Environ Health 3:140-146. CMA 007763 Spirtas R, Van Ert M, Gamble J, Wolf P, Mctlichael AJ (1976). Toxicologic, industrial hygiene and epidemiologic conside rations in the possible association between SBR manufac turing and neoplasms of lymphatic and hematopoietic tissues In: Proceedings of NIOSH Styrene-Butadiene Briefing. US Department of Health, Education and Welfare Publication (NIOSH) 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 0077&4