Document kDnz5Q6LV5RknLp4w4bLZgMXn

R&S 109314 t - ft r BIO-MEDICAL RESEARCH _ " DOCUMENT DESCRIPTION FORM 63 68 69 76 Duplicate.in all cards:--?> /f^r7 0003318 year as-1961- File number [Right justify [Numeric only] Author(s), as Last Name FS (No Punctuation) and coden for journal as JAMA preceeded by one blank space 1 * 20 21 4 /i f > / + y, ' f A' > ^ 40 4160 r ) ; ,4- 77 78 I Ml I Sub-Index Code 61 62 11 12 13 Title of Report; end with space-hyphen-hyphen-space. Follow with Index Terms, separated from each other with comma-space. Avoid other punctuation; 61 62 jr 22 23 24 .y Source (Journal, Vol., Number, Pages, Date ) 12 Ce 6Y / '? /'-/Yf ?~! / :V 61 62 31 32 Brief Summary 12 10 SUMMARY: 61 62 61 62 63 64 Vol.69, no.2, 1978, p.151-162 3900218 Institute of Industrial Medicine - University of Padua - Dir.: Prof. M. Crepe 33 fi (/) <a w Ol FUNCTIONAL RESPIRATORY CHANGES UPON CHRONIC EXPOSURE TO MONOMERIC.AND POLYMERIC VINYL CHLORIDE C. Mapp, L. Fabbri, A. Rossi, G. Moro and G. Cervi A less investigated but nonetheless important aspect of the "vinyl chloride syndrome" is the field of respiratory function. LANGE (1974) found in 13 workers . afflicted with vinyl chloride syndrome that 8 of them had restrictive type func tional defects and attributed this clinical picture to a pulmonary localisation of the process of connective systemic scleroses. On the other hand already SZENDE et al. (1970) reported a case of pneumonokoniosis in a patient exposed to PVC powders: upon histological examination the micronodules were found to consist of "foreign body" type granulomae. FRONGIA et al. (1974) have experimentally repro duced on rats exposed in working environment to PVC powders the lesions already demonstrated on humans by SZENDE, thus confirming the hypothesis of the foreign body pathogenetic mechanism. This created a divided way of looking at the prob lem: on the one hand the possibility of pulmonary fibrosis caused by exposure to the monomer, with the picture of functional restriction, and on the other hand the picture of true pneumonokoniosis of "inert powders" caused by exposure to the polymer, very likely included within a mixed or obstructive functional picture. / an/ Although unable to consider the problem in/analytical manner either at the expe rimental or at the histological level, it was considered important enough to report the results of a study carried out on workers exposed to monomeric and polymeric vinyl chloride, emphasising the functional and radiological aspects. ENUMERATION OF CASES AND METHODS The present study coincided with the national epidemiological investigation pro moted by the. Chemical Workers Union (FILC): 2S8 workers were examined, these , were employed in the production of polyvinyl chloride in a factory situated in Ferrara. The field work was carried out in cooperation with. Service of Industrial Medicine of the Public Health Association of Ferrara. The average age of the subjects, all males, was 38.9 t 9.3 years, with 10.8 t 6.4 years of average length of service. R&S 109316 Each subject was tested in the following manner: - Survey of respiratory symptoms by means of the CECA questionnaire. - Complete clinical examination with anamnesis listed on the card proposed by FU - Complete spirographic examination, the determination of the residual volume was carried out with the helium dilution technoque. The Godart Expirograph _was used. The theoretical reference values were obtained by means of the CECA formulae (1971). A spirometric picture characterised by VEMS/CV x 100 lower than 65 % and/or residual volume higher than 130 % of the theoretical value was defined as obstructive; a picture characterised by a total lung capacity less than 80 % of the theoretical value was defined as restrictive. - Measurement of CO transfer by the "single respiration" method using the Morgan Transfer Test apparatus, model C. The inhaled gas concentrations were 13 % he lium and 0.28 % CO. In each case the air volume of the "wash-out" was higher than 900 cc and the sample volume was 900 cc. The period of apnea was always pre-programmed in 10". The inhaled volume was pre-programmed as 90 % of the vital capacity measured at the time of testing. This examination was al^^ performed before the spirometric examination which followed after at least 10 minutes to permit' complete wash-out of the inhaled helium needed for the trans fer test. On the average the alveolar volumes determined by single respiration (Va = Vi x exhaled ^ no- vary by values higher than t 10 % from the lung capacities measured with the dislution under stable conditions. All the transfer test values were corrected by the alveolar volume, obtaining in this way the DICO/Va ratio expressed in ml CO/min/mm Hg Co alv/1 This ratio (K) defined by COTES as "diffusion constant", was compared with the expected value obtained from the prediction formula established by the same COTES (1975) . The significantly reduced values were considered to be those which were lower than 90 % of the expected values. - The radiographs of the thorax were read according to the ILO UICC (1971) classi fication by a radiologist especially experienced in this field. The hands were also radiographed by the standard technique; in line with the instructions of the Epidemiological Commission on national scale, the X-rays were evaluated separately by two radiologists. - Ophthalmological examination of the fundus oculi. 1 - Digital photoplethysmography was carried out under basic conditions and after cold test (immersion of hands into 12 - 14C water for 10 minutes, repeating the plethysmographic test after properly drying the hands without friction). The reflection technique' was used here, the test consisted of graphic'recor ding by photoelectric cell the variations of the fleshy portion of the finger tips in transparency to light, primarily in relation to variations of blood content, for the purpose of indirect examiiiation of the anatomical-functional conditions of the arterial-capillary system of the fingers. The test result was considered pathological when the following conditions' were indicated: flattening of the curve or reduction of the width to below 25 % of the basic graph after the cold test. WORK ENVIRONMENT The factory in which the examined subjects were employed produces vinyl polymer from monomer. The production cycle comprises in a first stage the storage of the monomer produced elsewhere, the polymerisation in kettles using two processes, i.e., suspension and emulsion polymerisations, the drying of the obtained poly mer and its packaging. There is also a maintenance section and a section where the polymer is stabilised with lead salts. In accordance with the informations collected in the course of contacts with the workers and from the environmental data made available partly by the Works Management and partly by the local Healt: Authorities, we were able to assess the degree of exposure to monomeric vinyl chloride according to the following formula: Years of risk = (no. of high exposure years x 2) + (no. of medium exposure year? x 1.5) + (no. of low exposure years x 1) where "high exposure" was considered in the polymerisation phases, "medium" in the drying phases, packaging and internal maintenance, and "low" in the phases of external maintenance and stabilisation of polymer. The correction factors (2, l.S, 1) express the logarithm of vinyl chloride mono mer concentration as function of time, thus 100 ppm for high exposure, 30 ppm for medium and 10 ppm for low exposure. In this way, although with obvious approximation, we have overcome the problem of assessing the comprehensive exposure of a given subject during the time of employment in several locations with presumably different degrees of exposure. In line with this criterion we have obtained four classes of "risk years". R&S 109317 R&S 109318 Years of risk <5 5-15 15-25 > 25 Total Number of cases 38 88 80 52 258 14.7 34.1 31.0 20.2 100.0 Regarding the exposure to polymer in powder form we had to rely on very recent data which indicated the presence of powder up to 10 mg/m^ in the drying stage and up to 5 mg/m^ at the packaging of the final product. The investigation of the particle size distribution of the powders indicated a definite, but obviously a numerical prevalence of particles less than 5 microns in diameter. Finally, in the assessment of the respiratory function we have taken into consi deration the confusing factor of "tobacco consumption" by subdividing our popu lation into three groups: 1 - non-smokers (who have never smoked or are now non-smokers for more than 5 years) 2 - medium smokers (up to 20 cigarettes per day) 3 - heavy smokers (more than 20 cigarettes per day) 90 cases 135 cases 33 cases 34.9 52.3 % 12.8 RESULTS AND DISCUSSION Perusal of the results concerning the entire population (Table 1) immediately indicates the high prevalence of chronic bronchitis with previous history (88 cases, 34.1 %) and symptoms of chronic bronchial obstruction (sibilant respira tion in 27 % of cases), while the prevalence of bronchial asthma is low in all cases. Another important feature is that the prevalence of chronic bronchitis increases with increasing years of risk, stabilising above IS years of risk at a level of 37 - 40 %; also the correlation between the years of risk and dyspnea appears to be significant. Regarding the functional respiratory picture (Table 2), the most important fin dings are the high prevalence of subjects with residual volume above the maximum expected limit, this prevalence not being in linear relationship with the work exposure, and the significant percentage of subjects with mutual reduction of vital capacity and of VEMS, progressing linearly with classes of exposure, diffusion constant K is changed most in the first risk group and, at least parts, it is not connected with the concurrent functional respiratory changes.. From the radiological point of view (Table 3) the most significant finding is the high occurrence of clinical pictures which may be classified as p/s 0/1 according to the ILO (1971) classification. Micronodulation, classifiable as p 1/0, was indicated in a single case. To ascertain any differences between the incidence of alterations found in subjects exposed mainly to the monomer (kettle attendants) or to the polymer (workers employed in the drying and packa ging of polymer powders), we have separated the two groups, adding a third group exposed to monomer as well as to powdered polymers (Table 4). More frequent occurrences of chronic bronchitis and increase of residual volume (obstructive) were found among the workers employed in processes dealing with powders, while the difference in the percentage reduction of the total lung capacity (restric tive) appeared less evident. This finding is based, on the one hand, on a bron chial obstruction caused by polymer powders (bearing in mind the particle size distribution mentioned in conjunction with the environmental data), and on the other hand it is based on a restrictive change which can be presumably related to exposure to the monomer. To some extent this finding is confirmed by the radio logical result': the radiological pictures of initial micronodulation appear to be almost equally divided between the two groups in question, with a slight pre valence of micronodulation among the workers exposed to the monomer. R&S 109319 Table 1. Prevalence of syndromes and respiratory syndromes in the total popu lation as a function of the risk index Risk index <5 5-15 15 - 25 > 25 Total Chronic bronchitis 12 (31.6%) 25 (28.4%) 30 (37.5%) 21 (40.4%) 88 (34.1%) Dyspnea''" ~~ grades II-V 11 (28.9%) 27 (30.7%) 30 (37.5%) 28 (53.8%) 96 (37.2%) Sibilant respiration 7 (18.4%) 27 (30.7%) 18 (22.3%) 18 (34.6%) 70 (27.1%) Bronchial asthma 1 (2.6%) 6 (6.8%) 2 (2.5%) 4 (7.7%) 13 (5.0%) i P n. s. p < 0.01 P n. s. p n.s The expected spyrometric results were obtained on 251 persons; 249 had full residual volume. The DICO was measured on 233 subjects. In order to facilitate understanding of the nature and interpretation of these radiological pictures, in Table 5 we have presented the description of these. It can be seen that previous work risk is indicated in 9 cases wTiich, by itself, can justify the radiological survey; among the remaining 21 cases only S subjects were exposed to polymer powders, 8 were exposed only to monomer and 8 (employed * R&S 109320 in maintenance) were exposed to monomer as well as to polymer. The nine cases in which restrictive ventilatory change was observed were all exposed to moi^^tr or to monomer and polymer, while those with increased residual volume were mainly found among the maintenance workers. Because of only three cases of non-smokers, stratification on the basis of this factor is obviously not feasible. The distinct majority of findings relates to subjects with more than five years of exposure, not considered in terms of risk index. An observation which certainly merits attention is that among these 30 subjects two indicated concurrent acroosteolytic lesion and three indicated concurrent suspected or initial osteolytic lesion in the region of the distal phalanxes of the fingers. This seems to suggest a common pathogenic mechanism which may be related to exposure to monomer. Table 2. Prevalence of changes in spyrometric indices and in the diffusion constant in the population classified into risk groups (o = observed; t = theoretical; CV = vital capacity; VR = residual volume; CPT = total lung capacity) Risk index CVo/CVt 0.8 ' VEMSo/VEMSt 0.8 VEMS/CV 0.65 VRo/VRt 130% CPTo/CPTt 0.80 Ko/Kt 0.9 <5 5-15 15-25 >25 Total 3(7.9%) 8(9.4%) 19(25%) 16(30.8%) 46(18.3%) 1(2.6%) 7(8.2%) 9(11.8%) 11(21.1%) 28(11.2%) 0 5(6%) 1(0.7%) 2(4%) ' 8(3.2%) 10(26.3%) 34(40%) 24(31.6%) 13(26%) 81(32.5%) 1(2.6%) 7(8.2%) 11(14.5%) 7(14%) 26(10.4%) 9(26.A 15(18. sW 12(16.9%) 8(17.0%) 44(18.9%) P < 0.001 P < 0.01 p n.s. p n.s. p n.s. p n.s. Table 3. Prevalence of radiological signs indicating inter stitial fibrosis in the population grouped accor ding to risk index Exposure Number of cases 0/1 form <5 5 - 15 15 - 25 > 25 Total 37 3 ( 8.1 %) 86 12 (14.0 %) 80 7 ( 8.8 %) 52 8 (15.4 %) 225 30 (11.8 %) Considering now the response to the cold test, which was measured by the di ITphotoplethysmography, it is noted that 16 subjects (53.3 %) show-alteration this test; considering that changes were found in 15 % of the total population, further survey was indicated. 7 Table 4. Prevalence of pulmonary changes among the cases, sub divided into groups according to predominant exposure to monomer (A), to polymer powder (B) and to both (C) to varying extents Chronic bronchitis Obstructive change Restrictive change Pulmonary -----fibrosis .. A 26.9 % 20.0 % B 39.6 % 45.1 % C 35.5 % 33.8 % 15.4 % 5.9 % 9.8 % 13.4 % 11.3 % 11.1 % A-B per obstructive changes = 8,41063; p < 0.005' J3 (/> o CD CO ro Finally, the findings of sclerosis in the fundus oculi in 15 out of 26 subjects examined among those afflicted with pulmonary fibrosis (57.7 % as against 33 % in the total population), confirm the common pathogenesis of the phenomena under consideration. Arranged according to tobacco consumption, it is shown that' all indices of bron chial irritation are influenced by this factor in determining manner. Only the restrictive changes fail to show any relationship with this parameter Figs. 1, 2 and 3). When examining the prevalence of chronic bronchitis and of the obstructiv and restrictive functional changes, a certain relationship with the risk index is indicated only in the case of chronic bronchitis and the restrictive changes, with pathological aspects mainly in the smokers, while this is not indicated for the obstructive changes which appear much more distinctly influenced by tobacco consumption. The diffusion constant K was found to be changed in 44 subjects from which 41 were smokers, also this appears to be more influenced by this confusion factor. Fig. 1: Prevalence of chronic bronchitis among the cases grouped according to years of exposure and tobacco consumption (f = smokers; nf = non-smokers; anni rischio = years of exposure) Fig. 2: Prevalence of restrictive functional respiratory changes among the cases grouped according to years of exposure and tobacco consumption (f = smo kers; nf = non-smokers; anni rischio = years of exposure; restrittivi = restrictive changes) Fig- 3: Prevalence of obstructive functional respiratory changes among the cases grouped according to years of exposure and tobacco consumption (f = nonsmokers; nf = smokers; anni rischio = years of exposure; ostruttivi = obstructive changes) s R&s 109322 Table 5. Analytical description of individual cases (30) showing radiologic signs of the pulmonary fibrosis type characterised by micronodulation (form p/s 0/1) Smo- Section No. Age ker Exposure, months Previous exposure Spiro- Ko metry Kt Chron. Cold Aero- Scle bronch. test ostco- sis lysis fund 1 43 + polymer. 2 37 + polymer. 3 45 polymer. 152 38 78 4 35 4* polymer. S 44 polymer. 6 28 + drying 7 52 4- mainten. 6 156 52 246 S 44 + mainten. 168 9 51 + polymer. 264 10 51 packaging 168 11 36 + packaging 24 12 28 4- packaging 28 13 45 + polymer. 288 14 42 4* store 66 15 45 4- mainten. 128 16 49 - grinding 160 17 29 4- polymer. 72 18 29 4- stabiliz. 82 19 54 + packaging 178 20 43 21* 28 22 27 + mainten. stabiliz. + stabiliz. 180 60 36 23 44 4- mainten. 24 50 + mainten. 25 51 4- mainten. 180 204 276 26 47 4- mainten. 27 41 + mainten. 28 45 - polymer. 29 53 + store 30 46 4 mainten. 12 156 72 122 270 foundry (5 years) welder (15 yrs) welder (7 yrs) welder (7 yrs) welder (5 yrs) kiInman (4 yrs) - welder (8 yrs) - - asbestos (15 yrs) - RN R -85% NN - - ' NN - N -80% - 0N R N pres. RN - R N pres. -N - N -84% " NN " 0 -86% pres. NN - 0N - NN - 0 N pres. NN -- RN " NN N -90% - N N pres. 0N - 0 N pres. R N pres. NN - 0N - R N pres. 0N - R N pres. + - 4- + - " 4- -- -- 444* 44- 4- - 4- 4- - 4- 4- - 44- - - - " - " C S s - s c " - - 44- " - 4- " 4- + + -- -- 4* - 4- " 4* 4- - 4* 4" 4- + 44- Spirometry: N = normal; R = restrictive; 0 = obstructive. C = definite acroosteolysis. S = suspected acroosteolysis. * Radiological sign of chest X-ray incompatible with form p 1/0 To ascertain whether our conclusions would be in line with the data obtained for homogeneous group, considered as predominantly exposed section (to this end the population was divided into three groups, the first of these comprising the workers employed in the polymerisation, the second group covering successive phases of the production cycle with predominant exposure to polymer dust, and the third group comprising the maintenance workers) in Table 6 and in Fig. 4 we have represented the average observed values of the individual functional indices on the basis of the prediction formula: the result being severe shortening of the vital capacity and especially that of the total lung capacity in the first group which is mainly exposed to monomer, both in terms of quantity and duration, while in the case of the remaining two groups, the first of these exposed mainly to powders and the second irregularly exposed to powder and to monomer in their capacity as the members of these two groups engaged in maintenance work or in polymer stabilisation, the significant feature is the increment of residual volun While in the first case the severe shortening of the vital capacity is attribute to a reduction of compliance and thus of tKe inspiratory reserve volume possibly in direct relationship with pulmonary fibrosis, in the second case the severe reduction of vital capacity with concurrent increase in the residual volume is attributed to the impairment of the narrow air ducts; actually, in the course of the procedure used for determining the expiratory reserve volume a blockage of the narrow air ducts occurred and this, in turn, reduced the vital capacity in favour of the residual volume. -- The superimposable distribution of the radiological signs of pulmonary fibrosis among those exposed to monomer and to monomer plus polymer, supports the hypothi sis that the fibrosis could be related to the exposure to monomer. Table 6. Mean values of observed and expected spirometric indices in prevalence of pulmonary fibrosis in the population subdivided according to homogenous groups (CV = vital capacity; VR = resi dual volume; CPT = total lung capacity) Employed (67) in polymerisation Employed (53) in drying and packaging Employed (138) in maintenance and PVC stabilisation CV obs. 452 63 CV theor. 510 43 VEMS o. < 0.001 374 61 VEMS th. 393 39 R < 0.05 463 78 <502 60 0.005 378 71 389 50 n.s. 447 t 70 500 52 < 0.001 368 68 384 45 < 0.05 35 <n o <0 Cl\OJ CO 10 33 9 (/) o Table 6 (continued) CD CIOO 4* VR obs. 160 + 48 VR theor. 156 16 191 + 66 154 21 191 60 157 + 19 P n,,s. P < 0,.001 P < 0.,001 CPT obs. 612 + 89 CPT theor. 665 + 52 654 + 98 656 + 76 638 + 97 657 + 67 P < 0..001 P n..s. P n,,s. Fig. 4: Theoretical (right column) and observed (left) .values of total lung capacity (CPT) and residual volume (VR) in the three' homogeneous groups with different degrees of exposure (volumi polmonari = lung capacities; (polimerizzazione = polymerisation; essiccazione, insacco = drying, pack; ging; manutenzione, premix = maintenance, premix (stabilisation)) By comparing our values with those published in the literature, in the first plac a contrast with the data found by MILLER et al. (1975) is indicated: this author, examining a population exposed to both monomer and polymer, and assuming nonconvei tional functional parameters with very low confidence limits, concluded in favour of an obstructive functional defect.The only comparable finding is the chanson VEMS in all the population which is 45 % as against out 11.2 %, although wj^n res pect to the chronich bronchitis cases it is quite comparable with ours (30.5 % as against our 34.1 %). SUCIU et al. (1975), finding,a prevalence of the obstructive type changes, decided to identify the specific lesion caused by exposure to monomer as a systemic inter stitial fibrosis which, therefore, also affects the lungs. These aspects are well in line with the restrictive signs we have encountered in those exposed to vinyl chloride monomer; simultaneous exposure to other irritants (e.g. PVC powders) of similar particle size distribution to that we have found in the factory in question, will result, on the other hand, in a sign indicating im pairment of the narrow air ducts. T The extent of the specific functional impairment may be considered as limited, in fact we have found significant reduction of total lung capacity in 10 % of the total population and in 15 H of those employed in polymerisation, i.e., exposed only to monomer. However, we must not neglect the finding of the concurrent irri tative effect manifested in chronic symptomatic bronchitis enhanced by the sumption of tobacco and by the simultaneous presence of PVC powders, being ponsible for 40 to 50 % of the pathological findings. Confirmation of the hypo thesis of systemic fibrosis is provided by our findings of interstitial pulmonary fibrosis, acroosteolytic changes and functional peripherial circulatory changes 11 and changes in the fundus oculi in percentages higher than those found by RUTH LILIS (1975). Finally, the presence of micronodulations in one subject exposed predominantly to polymer powders (case no. 21, Table 5), in p 1/0 concentration, also justifies the finding of possible pneumonokoniosis caused by polymer, but this is an alto gether negligible aspect in comparison with the fibroses caused by the monomer, as our investigations have indicated. CONCLUSIONS Basically our findings permit us to draw three conclusions: 1) The specific functional picture of exposure to vinyl chloride monomer is rep resented by a consensual reduction of lung capacities which is in agreement with the clinical picture of interstitial fibrosis involving reduced lung function. The CO transfer test does not appear to be appropriate for the detection of this first change, considering that it is significantly influenced by tobacco consump tion. 2) In the radiological picture of the lung exposed to vinyl chloride monomer a non-evolutive interstitial fibrosis with micronodulations in very limited concent ration can be determined. The homogeneous spectrum of the initial radiological signs found in the various exposure groups leads us to conclude that the vinyl chloride monomer has a predominantly systemic effect, in comparison with the "foreign body" type reaction due to the polymer. 3) The specific changes due to exposure to monomer are, generally, moderate , botl in terms of prevalence and in terms of severity. Nevertheless, one must not dis regard the significant potentiation of effects between monomer, polymer powders and tobacco consumption which leads to the obstructive type clinical picture of lung function and to the appearance of the symptoms of chronic bronchitis. 13 CO o (0 CroO CJl