Document MG1EVR34vv0gR3kwRww22O25k

'6fL Original Articles Cancer Mortality of a Group of PpnaHipn \A/nrI/orc Fvnncorl C-'' '. * V-- - V V g _ * *-- w *^, Vinyl Chloride Monomer C. Theriault, M.D., Dr.P.H.f and F. Allard, M.D., M.Sc. The present stud/ was underrafcen to find out whether there was an excess of cancer mortality from causes other than angiosarcoma of the liver among a group of workers heavily exposed to vinyl chloride monomer (VCM). The mortality of 451 workers exposed to VCM for more than five years was compared with that of 670 workers from the same company who had not been exposed to VCM. The relative risk for digestive cancer was. s/gni/icant/y. higher than 1 (h.25, confkhnct* interval 269 to 14.52) in tho oxposvd group. Hu? staixhrdued mortality ratio (SMR) lor digestive cancer was also higher (SMR 259.26 p < 0.01) than that of the general population. No other cancer was in excess. Since the exposed workers are known to have had a cigarette smoking experience similar to that of those who fvere not exposed, it is concluded that the association between lung cancer and VCM exposure, if.present, is indeed rather small. Several studies have demonstrated that vinyl chloride monomer (VCM) produces angiosarcoma of the liver among people exposed at work.1'7 There is, however, much controversy about the capability of VCM to gener ate other types of cancer in man. One author,* using a proportional mortality ratio technique, described ex cesses of lung cancer (observed, 13; expected, 7.9; obs/exp 1.6) and brain cancer (observed, 5; expected, 1.2, obs/exp 4.2) in a group of 161 workers from two vinyl chloride plants.* Another author,* who studied the mortality of a group of 1,294 American workers exposed to VCM, re ported excesses of lung cancer (observed, 11 expected, *7.5; SMR 194, p < 0.05) and brain cancer (observed. 3; ex pected. 0.6; SMR 498, p < 0.05) among men who had had from the Department o( Soot *nd Preventive Medicine School of Medicine, level Uftrvemty. Ste-Fov. Quebec, Cenede. C1< 7P4 Thu rew"h was financed pertly under Crent No 7BOWS from the Cornell de le llec!*rche en Sente du Quebec their first exposure more than 15 years before their dea'h. While most authors have not been able to document a significant excess of any other cancer in their studies, they have noted that such an excess may exist. In order to better document the cancer mortality asso ciated with exposure to VCM. the present study of the workers of the Shawinigan vinyl chloride polymerization plant was undertaken. The miiin objectives of the study wsti* (1) to lomp.ire mortality among vinyl chloride? workers wuh the mortality of workers from a nearby industrial complex, and (2) to compare the moitality of the VCM workers with that of the general population The Shawinigan vinyl chloride* plant opened in 1943 as an independent company which produced both VCM and PVC (polyvinyl chloride) In 1958, it was merged into an industrial complex (to be used as the comparison group) of which it became the Cana dian Resins Division. In the late 1960s. the VCM produc tion ceased and only the polymerization process con tinued operation. In 1972, this division was sold and again became an independent plant. Over the years, the VCM and PVC productions fluctuated The average annual work force at the plant was 225 men In 1965, VCM pro duction was estimated at 90 million pounds and PVC at 60 million pounds.** In 1977, PVC production was 22 3 million pounds." Since several episodes ol unconscious ness among workers were reported, the level of VCM in the air at the workplace is believed to have been high dur ing this period. Ten cases of angiosarcoma of the liver have been reported since then.7 The industrial complex from which the comparison group was drawn comprises several divisions: a carbide division which produces calcium carbide and acetylene black; a chemicals division which produces several chem icals derived from acetylene: acetone, chloral, butanol, acetic acid, acetaldehyde, several acetates, solvents and resins; a stainless steel division which consisted of a small foundry and a division formed in 1957, which produced Journal of Occupational Medicine/Vol. 23, No. 10/0ctober 1981 671 URL 1227 ro URL 12273 Rg 1. -- Papulation under study. sulfuric acid, chlorine and cyanide. This complex started operations in 1927; some of its divisions opened at a later date; others closed in the late 1960s or early 1970s. The annual number of male workers averaged 1,000." Methods Population Vnder Study. -- All production workers .Those names appeared on the unions' lists or the com panies payrolls of the VC plant and the industrial complex between January 1.1948. and December 31,1972. consti tuted the pomihiirtn under tudv c*****M fold addresses, tcL-phone books. Quebec motor vehicles bureau, inquiries with fellow workers and families, searches in homes for retired persons) were used to trace these men, 18% of whom were still working for the same companies. Once identified, the worker himself or his next of kin (spouse, child or close relative) was questioned at home or at work by a trained interviewer. The ques tions permitted the reconstruction of a detailed occupa tional history within and outside the companies under study. Questions were also asked regarding smoking habits. For each deceased person believed to have been exposed to VCM, the occupational history was confirmed with the help of a fellow worker. The men whose number of years of work for these companies, as established through occupational histories, did not exceed five were removed from the study. The re maining population was then subdivided into three groups The first group (known as the unexposed cohort) consisted of men who stated they had not been involved with the production of VCM or PVC, or both, for a period greater than five months. The second group (constituting the exposed cohort) comprised men who declared they had worked on the production of VCM-PVC for more han five vears. Finally, th. third group consisted of the men who had worked on trv. prc.JucV''1" of VCM-PVC a period ot six months to five years. This group was ex cluded from analysis because it neither fulfilled the definition of the exposed nor the unexposed cohort Dala Sources. -- The vital status of these men was established as of December 31, 1977. Causes of death were determined from death certificates. They were coded according to the 8th revision (ICDA) by one of the authors, who was unaware at the time of the coding as to which group the man belonged. For cancer cases, a histopathological confirmation was sought on autopsy, biopsy or cytology reports contained in the medical files at the hospital. Information on Quebec's population and mor- 672 Mortality of Workers Exposed to Vinyl Chloride Monomer/Thgriault and Allard TaMa 1. - Agt Distribution at the Man in tho VCMExposed and Unaxpatad Cahorts as af Dacambar 31,1977 (Dacaasad Exckidad). *# 2b-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75 Total Expasad Ha. % 0 0 _ _ 1 0.3 28 7.1 75 19.1 96 24.5 10? 26.0 53 13.5 30 7.7 6 1.5 1 0.3 392 100.0 Unaxpasad Na. % 1 0.2 3 0.5 6 0.9 45 7.1 55 8 6 84 13.2 112 17.6 110 17.3 113 17.7 65 10 2 43 6.7 637 100.0 tality by cause, age and sex was secured from Statistics Canada for the year 1971. In order to ensure the validity of the results, only the causes of death which appeared on the death certificates were used in the.comparisons. Statistical Analysis. -- The results were analyzed using the "man-years at risk" method as described by Hill.** The number of person-years of observation was established for each five-year age group and for each five-year period between 1948 and 1977. The mortality in the exposed cohort was compared with that m the unexposed cohort according to the method of relative risk. The tests of significance used were those of Mantel, Haenszel'411 and Miettinen.'* " The observed mortality was also compared with the mor tality exp<- uc rrc.T. pwpuiauon ot ine Province oi Quebec according to the method of the standardized mortality ratio (SMK)14 fix* test of significance uuxl was tlx* one |h*M filx*d by liailar and Ldefcr '* Quality Control Procedures. -- A thorough occupa tional history was developed for workers who were ex posed within the VC plant. The questionnaires presented a detailed profile of the plant while specifying possible fobs within its major units. Before the beginning of the study, it was pre-tested with former employees. Interviewers who contacted the workers had received training by the same person and were supervised during the entire study. The completed questionnaires were re viewed weekly by one of the authors and missing infor mation was sought by telephone. Data entered in the computer were systematically checked against the origi nal questionnaires. Results As shown in Fig 1. the population under study originally comprised 1,659 workers. Of these, 48 men were untrace- able. leaving the number in the study population at 1.611 (or 97.1% of the original number) After the removal of the 156 men who had worked at the companies for a period not exceeding five years and the 134 men who had been exposed to VCM for a perod extending from six months to five years, the exposed cohort comprised 451 men and the unexposed one, 870 men. In the exposed cohort, the proportion of men who responded to the questionnaire for themselves was 84.3% in the unex posed cohort, this proportion was somewhat lower at 68.2%. The age distributions of the workers in the exposed and unexposed cohorts as of December 31,1977, reveals that workers in the uncxposed cohort (Table 1) were somewhat older. Since the industrial complex had been in operation for several years when the VC plant opened, the finding of older people in the latter cohort was predictable. Table 2 shows the distribution of the exposed workers according to their length of exposure and their observa tion period (time between first employment and end of follow-up). Among these. 61% (365 out of 451) had an ob servation period of 15 years or more. For 23% of them, the time elapsed between first exposure and the end of the follow-up period exceeded 29 years. The mean obser vation period for the exposed cohort was 22.6 years. Table 3 gives the diagnosis at death and the diagnosis after histopathological review of all the cancer cases found in the exposed group. On the death certificates, eight cancers of the liver were reported. The histopatho logical review rejected one of them as being a cancer of tic .Icv.kv o' .he Kjt added another as an inr^vre'**1*' rfi^nose-.' ,,ancer ot uw (-ntoneal cv.iT, All <Hghl oiM ivs of tlx* lvt*r lurixxl out to lx* nngim.ir- toma of tlx* liver. It is noted (hat two more angiosar comas of the liver were certified as cirrhosis on the death certificates and were considered as such throughout this study. Table 4 compares the mortality of the exposed workers with the mortality of the unexposed workers. The con fidence interval (95%) of the relative risk indicates that there is a significant excess of mortality due to cancers of the digestive system in the exposed group (KR 6.25. con fidence interval 2.69 to 14.52). There is no excess in the other causes of death. Table 5 shows the standardized mortality ratios (5MR&) for the exposed workers in comparison with the entire population of the Province of Quebec. The SMR for all causes is 83.02, thereby showing no excess of death in the exposed cohort. Although the SMRs for all cancers, respi ratory system diseases and digestive system diseases ex- URL 12274 Tabta 2. -- Distribution a! Expasad Workors by Langth of Exposure and Observation Period. Exposera (Taarsl 5- 9 10-14 15-19 20-24 25-29 304Total Oftsonratian Period (Yaars) 5-1 10-14 15-19 20-24 25-29 30 4- 30 28 7 40 2 -- 28 26 19 17 _ 17 35 19 ___ ___ 22 24 ___ ___ -- -- 34 _ ------ 4 5 8 15 33 38 30 56 50 116 96 103 Journal ot Occupational Medicine/Vol. 23, No. tO/October 1981 Tata! ill 95 79 61 67 38 451 673 Table 3. -- Age at Death, Diagnosis on Death Certificate and Diagnosis on Hisloiogical Review of the 20 VCM-Exposed Workers Who Died of Cancer. Case Number 1 i 3 4 5 6 7 b 9 10 11 12 13 14 15 16 17 16 19 20 Death Certllicate Cancer of the irver Cancer ot the intestine Carcinoma of the trachea Angiosarcoma ol ihe peritoneal cavity Cancer of (he long Cancer of the hver ry-*f m ih* ik* vancer of the prostate Angiosarcoma ol the liver Cancer of the pancreas Adenosarcoma of the intestine Hepatoma Cancer of the liver Cancer of ihe pancreas Chondrosarcoma Hepatoma Primary cancer of the liver Cancer ot the digestive track Cancer ot the biliary ducts lymphoid leukemia Histological Review Cancer ot Ihe sigmoid flexure ot the colon Metastatic cancer ot the colon Carcinoma of the trachea Angiosarcoma of the liver (no review) Angiosarcoma ol the liver p* IUir Cancer of Ihe prostate Angiosarcoma ol the liver Epithelioma ol the head ol the pancreas Adenosarcoma of the mleslme Angiosarcoma of the liver Angiosarcoma ot the liver Anaplastic epithelioma of the pancreas Chondrosarcoma Angiosarcoma of the liver Angiosarcoma of the Over Cancer of the cecum Cancer of the head of the pancreas Lymphoid leukemia Age at Death (TWS) 73 56 50 41 54 42 57 04 o2 40 53 $3 S3 59 43 46 53 52 54 46 Total Expeture (tears) 15 16 15 11 16 19 17 * >P> 18 6 25 24 22 29 7 22 5 26 12 21 latency Period (Years) 26 17 15 11 16 19 23 2n 23 13 28 24 23 30 10 22 12 26 12 21 ceed 100, they are not statistically significant. On the other hand, deaths by accident and violence are signifi cantly tower (p < 001) As for specific cancer deaths, a significant excess is noted for cancer of the digestive system only This excess is accounted for exclusively by cancer of the liver (6 cases observed versus 014 expected, SMR 5,714.29) No other cancers are in excess. The cancer mortality among the workers who were still liivc 15 yi>irs aftiar IIw>tr first cxfKjsurt* shows the same results as tlnr mortality in the entire group, namely that only cancers of the digestive system are in excess in the exposed cohort (Table 6). Discussion Difficulties encountered in comparing the mortality of a group of workers with the mortality of a whole population are well documented. They are termed: "healthy population selection effect," "survivor population effect,"1* "ethnic/cultural/social characteristics." They are believed to underestimate the actual mortality of a group of workers and therefore to underscore the effects of the risks to which these individuals are being exposed at work. There are no easy ways to avoid such difficulties. One method would be to compare a group of workers with another group of workers with the same characteris tics except for the exposure to the risk under study. The problems encountered in so doing are no easier Although the group most sim.lar to industrial workers is probably another group of industrial workers from the same town, it is almost impossible to think of a group of industrial URL 12275 674 Table 4. -- Deaths Observed in the VCM-Exposed and Unexposed Cohorts, Age-Adjusted Retalive Risks and Confidence intervals of tho Relative Risk. Causa al Death All cancers (140-209) Mouth and pharynx (140-149) Digestive (150-159) Respiratory (160-163) Bone. skm. connective (170-173) Urogenital (165-169) Eye. CNS leukemia (190-192) (200-209) Other cancers Cardiovascular Respiratory Digestive Accidents and violence (390-456) (460-519) (520-577) (800-899) Others Total Ne. of Casts Exposed Uitexpesed 20 52 02 14 9 2 20 22 17 02 14 06 25 124 6 15 4 12 2 t5 2t 15 59 233 Relative Risk 1.46 -- 6.25 0.36 1.67 0.83 -- M5 -- 0 80 0.61 1 44 0.51 0.5? 1.07 5* Cenfktence Interval el the Relative Risk 0 64- 2.61 -- 2.69-14.52* 0.08- 1.58 0.21-12.99 0.10- 7.ID -- 0.07-17 80 -- 0 47- 1.36 0 44 9 35 0 49- 4 25 0.21- 1.24 0 14- 2.39 0 79- 1.45 *$igniticani according to Miettinen's test17 fOne cause unknown Mortality of Workers Exposed to Vinyl Chloride Monomer/Tti6riault and Allard Tib* 5. - Observed and Expected* Numbers M Deaths la the VCM-Expesad Cehorl and Standardized Mortality Ralios (SMRs). Cmii el DMtk All cancers Moult) and pharynx Digesiive Respiratory ftone, skin, connective Urogenital Eye. CNS Leukemia Other cancers Cardiovascular Respiratory Digestive Accidents and violence Others Total (140-709) (140-149) (150*159) (160-163) (170-173) (185-169) (190-192) (200-209) (390-458) (460-519) (520-577) (800-999) Observed 20 0 14 2 2 1 0 1 0 25 6 4 2 n 59 Expected 16.37 0 64 5.40 578 6.38 1.33 0.60 1.67 0.54 31.67 3.21 3.65 10.58 5.40 71.07 8MR 122.17 -- 259 761 34.60 526.32 75.19 -- 59.88 _ 76 94 166 91 103.90 16.901 37.03 83.02 Expected numbers obtained trom 1971 males Quebec death rates applied to person-years in each age group tp< o.or* }One cause unknown workers not exposed to some kind of carcinogenic risks. In the present study, the authors decided to compare the exposed workers with both the general population and a group of unexposed workers. It must be noted that among the unexposed workers, no causes of. death, were found to_be_in excess,when their mortality was compared with that of the general population. , Tlx* comparison of the mortality of the exposed and the unexposed workers gave results similar to the one reached by the comparison with the general population. The nuWiber of cancer of the digestive system was sianifi- c&ntly higher in the.exposed cohort. No other cancer was in x<i*ss and <*v<>n to lx* a (kffk.it (not stativ In .illy signilii anl| in rtfspiratory cancers. Considering the fact that animals experimentally ex posed to VCM have developed not only angiosarcomas of the liver but also malignant tumors of several organs (skin, lung, bone, Zimbal glands, kidneys, mammary glands)111111 and since several epidemiological studies on VCM-exposed workers have found an excess of lung cancer.1* the results of this study of heavily exposed men are surprising Three questions can be raised One con cerns the ascertainment of the population. In retrospec tive studies conducted from old company or union rec ords it sometimes happens that records of people who die or leave get lost. These losses could account for the low cancer rates observed. But this is a remote possibility, since the approach followed was a historical-prospective retrospective one, which began with old lists of workers composed in 194ft and 1952 and followed almost every one through time, adding new workers as they first ap peared on more recent lists. This was done without knowl edge of exposure to VCM A second reason for low lung cancer rates could be a bias in the classification of persons as exposed or not ex posed. The classification was made essentially on the basis of personal recollection for living persons and by family members with confirmation by co-workers for (hfceaMfd |mts<xy lo minimize such bias, much attention had been given to the occupational history (with indica tion of the buildings the subject had worked in) and workers with VCM exposure shorter than five years were rejected. There remains the possibility that some of the men who died of liver cancer, had they lived longer, might have developed lung cancer. The small size of the population under study increased the probability of not detecting an excess that was actual ly present. This was a case where "the number of person/ years at risk may be too small to detect an increased risk of cancer."1* It was particularly true for rare cancers such as cancer of the brain and cancer of die lymphatic system. Inasmuch as cancer of the lung was concerned. Table 8. -- Relative Risks and SMRs far Cancer Deaths Amtng Men | URL 12276 Cancers All cancers Mouth and pharynx Digestive Respiratory Bone. skin, connective Urogenital Eye. CNS Leukemia Other cancers (140-209) (140-149) (150-159) (160-163) (170-173) (185-189) (190-192) (200-209) he. 15 0 11 2 0 0 0 *p<0.01 Journal of Occupational Medicine/Vol. 23. No. 10/October 1961 JMrtve Risk 1.30 -- 5 68 0.35 -- 0.82 -- 0.59 -- M% CenMenee Marvel M the Relative Risk 0.97- 174 -- 272-11.58 0 25- 473 -- -- -- -- -- SMR 129 -- 281* 47 -- -- -- -- -- 675 the situation was somewhat different When one applies the Quebec lung cancer death rate after adjustment for age to the exposed cohort, the probability of finding an excess twice as high as in Quebec was 73%. This proba bility would have been 99% had the excess been three times as great in the exposed group.*1 In view of the fact that the smoking experience of the exposed workers was similar to that of the unexposed and considering that the subjects in this study are believed to have been heavily exposed to VCM, it seems reasonable to conclude that the excess of lung cancer associated with VCM exposure, if present *$ indeed rather small. Itir author! wi*6 to e*pr** their gratitude to the Isllmnnn who contributed Ni ih<\ study MiitiN. union retNcMMUliWN and nwiuiffTMtil tn-rvjnnrl cii the lontlMrmn. CarMriMii ttviim and Chemical*, Shawmigan Chemical!. HF GwaktihaftH <.ult Canada. l)r<. h Hurra and I iahia, e|>xk-niolOK<stv and Dr I I>+mii', iMtlMdowK.), lor th>-ii hi4p and advice. Ihe several hospitals cotv lacted. and the M-veral per*on* who atinted with the collection o4 information and the writing at this artKle deferences 1. Creech |l )r and lohnson MN Angiosarcoma of liver in the man ufacture of polyvinyl chloride / Occup Med 14150-151. 1974 2 labenhaw IR and Galley WR Mortality study of workers in the manufacture of vinyl chloride and its polymers. / Occup Med U 509-518. 1974 3 Nicholson WJ. Hammond EC. Seidman H. et al Mortality experi ence of a cohort of vinyl chloride polyvinyl workers Ann NY Acad Scr 24* 225-230. I^S 4 Duck IIW. Carter IT. and Coombcs 11 Mortality study of workers m a (mlyvinyl-t hlrrrtdi- production plant Lancet 21197-1199, 1975 5 Byfen D. Engbolm G, Englund A. and Wesierholm P Mortality and cancer morbidity in a group of Swedish VCM and PVC production workers Environ He*/* Perspec117167-1 m *07*. b FotAUstlkUiiit-irr Mortality experience of workers exposed to .inyj IiIiniiIi- iiwwiimih-i m tlw- in.Htiil.ii litre >l |M>iyvinv< Hkimlr in r.ie.ll liiil.im nI 1 Inil Mtsi M I Hi. 1977 7. Delorme F and Thdriault G: Ten cases ol angiosarcoma of the liver in Shawtntgan. Quebec. / Occup Med 20.338-340. 1978 8 Mornon R, Peters |. and lohnson M Proportional mortality among vinyl chloride workers Lancet 2.397-39B. 1974. 9 Waxweiler )R. Stringer W, and Wagner JJ: Neoplastic risk among workers exposed to vinyl chloride Ann NY Acad 5ci 270 40-48. 197b 10 Special Report by the Editors PVC aims for a bigger share in plastics Can Cham Process 49.41*44. 1965. 11. Conseil des Sciences du Canada: Vue d'ensemble des dangers de la contamination par le chlorure de vinyle au Canada. Quebec Science (SupplJ .1 -24.1977. 12 LaRochellef: Shawinigan depuis75 ans. Ateliers de I'lmprimerie Publicity Piquet Enr. 197b. pp 497-525 13 Hill ID: Computing man years at risk. Br / Prev Med 24:132-134 1972. 14. Mantel N and Haenszef W-. Statistical aspects of the analysis of data from retrospective studies ol disease / Natl Cancer fn$r 22 710-748. 1959 15 Mantel N: Evaluation ol survival data and two tank order statis tics arising in its consideration. Cancer Chcmotber Rep 50163-170, 1966 16 Miettinen OS: Standardization of risk ratios Am / tpidemiol 94:383-388. 1972. 17. Miettinen OS: Simple interval-estimation of risk ratio. Am / tpidemiol 100:515-514.1974 18 Gaffey WR A critique of the standardized mortality ratio. / Oc cup Med 3 157-160. 1976 19 Bailar fC and Ederer F: Significance factors for the ratio of a Poisson variable to its expectation. Biometrics 20 639-642, 1964 20 Fox A| and Collier PF. Low mortality rates in industrial cohort studies due to selection for work and survival in the industry. Bt I Prev Soc Med 30 225-230,1976 21 Vida PL: Cancerogenic Effect of Vinyl Chloride. Vol. 29. X Inter national Cancer Congress, Houston. 1970. 22 Viola PL, Bigotti A. and Capulo A Oncogenic response ol rat skin, lungs and bones to vinyl chloride Cancer Res 31510-519, 1971 23 Maiton1 C and Lefemme G: Cancerogenicity two assays of vinyl chloride: Current results Ann NY Acad Sei 246195-218.1975 74 Waenner IK Vinyl utln tJ* and oulmonary cancer. / Env Pathol To~icol 1 361-362. 19/8 21 ii ll 1, ,'<!, ,111.1 K-irrli H < <1111 <-r i-pirli-uiiologH Mirvcii- lanri- Ml the Dul'unt Cump.my. / Occup Mill 20 725-740. 1978 URL 12277 Reducing Financial Risks There is too little evidence that the nuclear industry, which was never very good at calculating its own interest, is seriously contemplating the effect of another Three Mile Island on its future -- or its fortunes. The industry has already returned to complaints that the safety bureaucracy is nitpicking it to death, running up construction costs and delaying licenses The latest complaint is that, in the aftermath of the TMI accident, NRC diverted safety reviewers to deal with operating reactors and felt behind in ap proving new licenses. There is a kind of tunnel vision in the failure to see the connection between safety and the special financial risk involved in nuclear investment. To use the current energy crisis to avoid safety requirements is to ignore the fact that safety is essential to protec ting the heavy investment in nuclear power. Some hope lies in the fact that, although the industry thinks safety requirements are a pain in the neck, they may be forced to look at them as an investment in financial public relations to alleviate the bankers' skepticism -- Vector Cilmtky, Commissioner, the Nuclear Regulatory Commission, a* Quoted in "Notable and Quotable," tn The Wall Street Journal. May 21.1961 676 Mortality of Workers Exposed to Vinyl Chloride Monomer/Th6riault and Allard REFERENCES 1. Taylor, }. S. 1 979. Environmental CMoraene: Update and Overview. Ann NY Acad Scl 320: 295*307. 2. Morse, 0. L.; Baker, Jr., E. L.; Kimbrough, R. D.;and Winemart, III, C. L. 1979. Propartil-Chloracne and methomyl toxicity in workers of a pesticide manufacturing plant. Clin Toxicol 15: 13*21. 3. Sundstom, G.; Jansson, B.; and Renberg, L. 1978. Determina tion of the toxic impurities 3,3',4,4 'tetrachloroazexybenzene in commercial diuron, linuron and SAdichloroaniline samples. Chemosphert 12: 973*79; Bunce. N, J.; Corke, C. T.; Merrick, R. L.;and Bright, |. H. 1979. 3,3 ,4,4-tetrachloroazobenzenc as a contaminant in commercial pfopanit. Chemosphert 5: 283*84. 4. Bartha, R.; Linke, H. A. 6.; and Framer, D. 1968. Pesticide transformations: production of chloroazobenzeqes from chloroanilines. Science 161: 582*83. 5. Poland, A.; Glover, E.; Kende, A. S.^DeCamp, M.; and Giandomenico, G. M. 1976. 3,4,3 ',4 -tetrachloroszoxybenzene and azobenzene: potent inducers of aryl hydrocarbon hydroxvlase.Sc/ence 194: 627-30. 6. Hsia, M. T. S.; Bairston, F, V. Z.; Shih, L. C. T.; Pounds, |. G.; and Allen, J. R. 1977. 3,4,3 ,4*tetrachloroazobenzene: A potential environmental toxicant. Res Commun Chum Pathol Pharmacol 17: 225*36. 7. Hsia, MVT. S., and Burant, C. F. 1979. Preparation and spectral analysis of 3,3`,4,4'tetrachloroazobcnzene and the correspond ing azaxy and hydraxo analogs. / Assoc Off Ana/ Chem 62: 746*50. 8. Taylor, J. $.; Wuthrich, R. C.; Lloyd, K. M.; and Poland, A. 1977. Chloracne from manufacture of a new herbicide. Arch Dermatol 113: 616-19, 9. Kimbrough. R. D.; Carter, C. D.; Liddle, J. A.: Cline, R. E.; and Phillips, P. . 1977. Epidemiology and pathology of a tetrachlorodibenzodioxin poisoning episode. Arch Environ Health 77*86. 10. Adams, E. M.; Irish, D. D,; Spencer, H. C.; and Rowe, V. K. 1941. The response of rabbit skin to compounds reported to have caused acneform dermatitis. Ino Med 10. {Ind Hvg Sec) 2: 1-4. 11. Schwetz, B. A.; Norris,). M.; Sparschu, G. L.; Rowe, V. K.; Yehring, P. J.; Emerson, J. L.; and Gerbig, C- 1973. Toxi cology of chlorinated dibenzo-p-dioxins. Environ Health Perspect 5: 87*99. Effects in the Rat of Inhaling PVC Dust at the Nuisance Dust Level (10 mg/m ) c. ro troo --j CO R. J. RICHARDS, Ph.D. F. A. ROSE, Ph D. T. D. TETLEY, Ph.D. Department of Biochemistry University College .'diff, Wales tied Kingdom L. M. COBB, Ph.D. MRC Radiobiology Unit Harwell, Oxon United Kingdom C. J. HARDY Department of Inhalation Toxicology Huntingdon Research Centre Cambs., United Kingdom ABSTRACT. Rats inhaled a paste polymer polyvinyl chloride dust at an aerosol concentration of 10 mg/m3 for 6 hr/day, 5 days/wk for a 15-wk period. A small num* ber of randomly scattered lung lesions were detected at 15 wk; these lesions were also present 15 wk after exposure to polyvinyl chloride had ceased. Few if any biochemical changes were detected at the alteolar surface in lung tissues or other organs of polyvinyl chloride-exposed rats. It is therefore concluded that at "nuisance" dust level this form of polyvinyl chloride polymer exhibits a weak biological reactivity. DURING ONE STAGE in polyvinyl chloride (PVC) manufacture the material exists as a fine, easily respirable dust. Consequently, investigators have examined the effects of this dust on mammalian lung. 14 Archives of Environment*! Health URL 12279 The few experimental studies that have been reported present conflicting data on PVC toxicity. This may be due to the different formulations of PVC examined and/or differences of experimental designs. In the only previ ously reported inhalation study,' the authors suggest that continuous (24 hr) exposure of guinea pigs for 2-7 months in a PVC bagging plant resulted in the formation of granulomatous foci in the lung. The nature of the PVC used in that study-possibly a mixture of homopolymer and paste polymer-is not described, and the level of exposure is poorly defined. Using a simple in vitro technique of hemolysis it has been shown that different formulations of PVC exhibit differential biological potential, as assessed by their ability to react with red blood cell (RBC) membranes.2,* Thus, homopolymers are not hemolytic, whereas paste polymers containing surfactants (detergents) on their particle sur face produce extensive RBC damage in vitro. The chemi cal formulation of the detergent used in the preparation of the PVC polymer was, therefore, considered important in its hemolytic reaction.* Similar findings were reported by other investigators4'* who found that certain emulsion (paste) polymers were cytotoxic to rat peritoneal macro phages maintained in vitro, which is a test system consid ered by some investigators to be indicative of particle fibrogcnicity in vivo. These investigators,5 however, subse quently concluded that some paste polymers containing detergents produce a "false-positive" result in the in vitro system because the intratracheal 2-mg injection of the identical polymers into rat lungs produces no progressive fibrogenic response (unlike a quartz). All the polymers tested in experimental animals produce only a mild inflam matory response, and it was therefore concluded that PVC per se is an inert material.5 Intratracheal instillations of high doses (25 mg) of PVC have been shown to induce biochemical and histopathological changes in rat lung tissue;* other studies1 have indi cated that the cellular and biochemical effects at the alveolar surface and in lung tissue of instilled PVC particles are dose-dependent. However, aggregates of PVC dust given intratracheally, like many other materials given in this way, can produce a different, usually more vigorous, response from that produced by inhaled dust. Additionally, it is not possible to convert a single intratracheal instilla tion of a known volume of dust to a period of exposure at a multiple or fraction of the dust level, which means that for assessing safe occupational exposure levels, the results from intratracheal instillation studies are open to critical interpretation. The aim of the present study was to determine whether the inhalation of a paste polymer, PVC-7, containing the detergent sodium dodecyl sulphate,3'7 at "nuisance" dust level (10 mg/m3) would produce any alteration in the lungs of experimental animals. The parameters chosen for investigation included a study of the biochemical integrity of the alveolar surface by estimation of free cell number and enzyme activities, and determination of pulmonary surfactant levels and soluble protein. In addition to histopathological examination of the lung, DNA, and protein `synthesis' and hydrolytic enzyme activity of alveolar tis sue were monitored. MATERIALS AND METHODS Animals. Eighty 10-wk-old female albino rats of the Sprague Dawley C.D. strain (Charles River, U.K. Ltd., Margate, Kent) were used in this study. These were ran domly allocated to either the control or PVC-exposed group so that each group consisted of 40 rats. The rats were housed in groups of four, in polypropylene cages with stainless steel mesh floors. Food and water were sup plied ad libitum while the rats were in the cages. The room temperature was maintained at 20 2C, and light ing was controlled to provide a 12-tv light period each da\. Aerosol exposure. A paste polymer, PVC-7, which con tains sodium laur% * (dodccy I1 sulphate surfactant was used throughout the study. The PVC-treaicd animals were exposed to a mean aerosol concentration of 10 i.e., "nuisance" dust level (Guidance Note EH 15/77, Health and Safety Executive), on 5 days for 6 hr/day for 5 days/wk up to 15 wk. Groups of lOexposed rats were examined with control animals at 3, 9, and 15 wk after the experiment was initiated. One group of animals was maintained without further contact with PVC for 15 wk after being previously exposed to the dust for 15 wk. A nonexposed control group was also maintained during this time period. Exposures were carried out in a perspex, cubic, 240-L chamber which was operated under dynamic conditions at a slight positive pressure. The aerosol of PVC pariidc> was generated using a Wright dust feed mechanism (L. Adams Ltd.; Minerva Road, Chase Estate, London NW10). Following preliminary experiments to determine optimum operating conditions, a dust packing force of 0.2 tons was used. The mechanism was operated with standard canister liner at a gear ratio of 4 : 1 reduced. Total chamber air was supplied through the dust feed which was run at 1.05 kg/cm2 (25 L/min). The aerosol was introduced into the exposure chamber at the base center and then ascended through an area clear of holding cages to descend through the cages in which the animals were individually housed, and left the chamber through a series of holes at the base. The chamber was held in a fume cupboard which was at negative pressure with respect to the laboratory, and the exhausted dust was removed by an absolute filtration unit. Control animals were placed in an identical chamber, but were exposed only to the same compressed air as that used to operate the dust feed mechanism. Aerosol concentration was determined twice daily by gravimetric analysis of samples collected with an openface filter holder operated in the vertical position. Due to the extremely low aerosol concentration, a sampling rate of 10 L/min was required to ensure accurate assess ment of total chamber concentration. The particle size distribution in the chamber was measured using an Ander son mini-sampler. Treatment of animals prior to biochemical analyses. In the biochemical studies six exposed and six control rats were examined at each chosen time interval and treated identically. Each animal was given an intravenous tail vein injection of 75 *xCi of [methyl-3H]-thymidine (52Ci/mmol) and 2.5 *rCi of L-[U-14C]-proline (282,5 mCi/mmol) and left finuary/February 1981 (Vol. 36, No. 1) 1$ Table 1.-Cellular and Biochemical Studies on Rati Expaaed to tO mg/m3 PVC Dust for Different Time Periods Exposure Period/ Animal Group Lung Weight/ Body Weight Ratio x 102 Number Free Cells/Animal X 10~* Pulmonaryt Surfactant mg/AnI mat Pulmonary! Lavage Protein mg/ Animal Acid RNAase units/10 Cells Acid RNAase unlts/g Lung ONA mg/g Lung 3 Weeks Control PVC-Ex posed 0.53 (.086) 0.55 (.082) 6.71 ( 0.93) 8.86 {1.52) 0.50 0.52 2.25 2.62 0.68(10.12) 0.69 (1 0.29) 74 (10) 75 (19) 3 Weeks Control PVC-Exposed 0.47 (.036) 0.48(1.037) 19.35 (1 4.64) 13.79 (14.63) 0.60 1.50* 3.19 3.96 1.17(1 0.27) 1.39 (0.31) 108(112) 104 (12) 15 Weeks Control PVC-Ex posed 0.43 (.023) 0.40 (.045) 11.00(1 3.61) 11.00 (1.08) 0.66 0.62 2.86 3.11 0.90 (10.31) 1 TO (10.21) 83( 5) 104 ( 16}* IS* Wk 1S Wk Clearance Control PVC-Exposed 0.39 ( .028) 0.41 (1.063) 9.26 (1 2.93) 11.59 (1.97) 1.28 1.20 3.50 4.13 0 96 r* G22) 0.72 (0.23) NOTE: Numbers within parentheses refer to standard deviation. 'Significantly different from control. * Values represent mean of pooled samples from sia rats. 45( 8) 50| 9) 4.54 (+0.76) 4.06 (0.43, 4.93 (1.07] 5.30(10.8?) 4.0t(0.87) 4-78 (0.32) i 4.23 (0.25) 4.27 { 0.29) for exactly 1 hr. They were then sacrificed by intraperitoneal pentobarbitone injection, a blood sample was then removed from the hepatic portal vein, and the lungs per fused via the heart with 0.15 M NaCI to remove blood from the vascular bed. The lungs were removed from the pleural cavity and lavaged six times with 0.15 M NaCI, after which they were dried between paper towels and weighed. The lavaged lung tissue and pooled washes were kept on ice prior to further treatment (see below). Other tissues taken for examination were the liver, spleen, kid ney and sections of the gastrointestinal tract which were stored frozen until required. fractionation of (avage fluid and biochemical analysis. The free cell population from each animal lavage was obtained by centrifugation at 300 g for 20 min at 4C. The supernatant fraction from six rats in each group was pooled and centrifuged ax 1000s for 1 hr at 4C. The supernatant fraction from this centrifugation contained the majority of soluble alveolar lavage protein.* The pellet was resuspended in 4 M NaCI, mixed well, and centrifuged at 1500g for 25 min at 49C, and the resulting separation gave a pellicle of lipoprotein-rich material, designated pul monary surfactant, which floated to the top of the tube. This was collected, dialyzed against distilled water, freezedried, and weighed.9 The free cell population was counted and the levels of acid RNAase and acid protease were determined as described previously. The incorporation of [3H]-thymidine into tissue DNA and [14C]-proline into tissue protein was determined as follows. Body tissues were homogenized in 0.15 M NaCI and samples suspended in a final concentration of 0.2M perchloric acid (PCA) for 1 hr. The mixture was centrifuged at 1000g for 20 mtn. and the supernatant, containing free label, discarded. This procedure was repeated once more and the resulting pellet was then resuspended in 0.5 M PCA at 70C for 20 min. to solubilize the DNA. The supernatant derived from centrifuging this mixture at 1000 5 for 20 min. was stored and the process repeated. The supernatant fractions were pooled and samples taken for chemical analysis of DNA and direct counting of [3Hj label. The remaining pellet was suspended in distilled water and samples digested in 1 M NaOH to assay for protein content or taken up in Soluene for determination of [14C] radiolabel. The efficiency of counting was determined by using internal standards and results were expressed as disintegra tion per minute of incorporated radiolabel per mg DNA or protein for each tissue examined. Histopathology. The trachea and lungs from four con trol and four PVC-exposed rats were removed after the rats had been killed by exsanguination under deep pento barbitone anaesthesia. 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Note aggregation of foamy macrophages and hyperceliularity of adiacent alveolar wall (oitoho). Hematoxylin and eosin stain (X 250). surfaced particles that filled foamy macrophages stained red with modified Sudan IV, indicating that they were PVC dust.13 Fifteen weeks after the final exposure (30 k from commencement of the experiment), the lungs ' control animals appeared normal, while those previ ously exposed to PVC showed no significant change in the lesions detected at 15 wk (termination of exposure). DISCUSSION The results show that a paste polymer preparation of PVC dust inhaled by rats at "nuisance" dust level (lOm^m3) for 6 hr/day, 5 days/wk, produces small, randomly scat tered, lung lesions after 15 wk of exposure. These lesions are characterized by hyperceliularity of the interstitium of the alveolar walls in areas adjacent to macrophage aggre gates containing PVC. In addition, the lesions persist 15 wk after the cessation of animal exposure to the particulate. The PVC-induced lesions, however, show only minimal increase in collagen and reticular fiber formation, with no evidence of extensive fibrotic reaction. Simitar conclusions are reported by other investigators* who studied the effects of intratracheal instillations of different PVC formulations. The results of the current histopathologica! study there fore suggest that at "nuisance" dust level PVC has a rela tively weak biological reactivity, and this conclusion receives further support from the biochemical investiga tion. While PVC-exposed animals have elevated levels of pulmonary surfactant and show a decrease in lung protein `synthesis' 9 wk after exposure, the presence of a mild respiratory tract infection in all the animals during this time period prevents the establishment of any definite con clusions. Thus relatively few, if any, biochemical changes in PVC-exposed rats are detected at any exposure period-- either at the alveolar surface, the lung tissue, or other body 18 Archives of Environmental Health organs. Such results are in contrast to previous inhalation studies where rats exposed to 12 mg/m3 chrysotik asbestos for 5 days/wk for 15 wk have elevated free cell numbers (2-3 X control animals) free cell and lung enzyme activity (3-10 and 1-6 X control, respectively), and pulmonary sur factant (12 X control).* Elevations in pulmonary surfactant and free cell numbers are also detected in rats inhaling amosite asbestos and fiber glass (12 mg/m1, 5 days/wk, for 8 wk).1* With dusts of "high" biological reactivity these biochemical changes at the lung surface persist with the progressive pathological development of lung disease. In summary, the present short-term study indicates that at "nuisance" dust level one form of paste polymer PVC has a weak biological reactivity, only detectable by histopathological examination, which reveals a small number of lung lesions in experimental animals. It is not possible at this time to interpret this finding in terms of the lesion likely to arise in man under similar conditions of exposure. Drs. Richards and Tetley would like to thank the Medical Research Council for financial support. We are also grateful to the Huntingdon! Research Centre for the provision of inhalation expo* lure facilities. Submitted foi publication November 14,1980; revised; accepted for publication December 8, 1980. Requests for reprints should be sent to: Dr. R. J, Richards, Department of Biochemistry, University College Cardiff, P. O. Box 78, Cardiff CF11 XL, U.K. REFERENCES 1. Frongta, N.; Spinazolla, A.; and Burarelli, A. 1974. Lesioni Poimonari sperimentali da inalazionc prolungata di poiveri di PVC In ambiente di iavoro. Med Lav 65: 321-41. 2. Richards, R. Desai, R,; Next, P. M.; and Rose, F. A. 1975. Biological reactivity of PVC dust. Nature 256: 664-65. 3. Richards, R.).; Desai, R.; and Rose, F. A. 1976. A surface* active agent Involved In PVC*induced haemolysis. Nature 260: 5>54. 4. Pigott, G. H- 1976. In vitro Studies of a range of formulations of PVC. Polymer Preprints 19: 29-34. 5. Pigott, G. H., and Ishmael, J. 1979. A comparison between in vitro toxicity of PVC powders and their tissue reaction in vivo. Ann Occur Hyp 22: 111-26. 6. Agarwal, D. tC; Raw, j. 1.; Srivasuva, $. P.; and Seth, P. K. 1978. Some biochemical and histopaihologica! changes induced by polyvinylchloride dust in rat lung. Environ Res 16: 333*341. 7. Tetley, T. 0.; Rose, F. A.; and Richards, R. ). 1980. Biochemi cal and cellular reaction of PVC paste polymers and latex following Intratracheal instillation into rats. Inflammation (in press). 8. George, G., and Richards, R. ). 1979. Preliminary studies on the isolation, separation and identification of pulmonarylavage proteins from the rabbit. Biochtm Soc Trans 7: 1285-87. 9. Tetley, T. D.; Next, P. M.; Richards, R.and McDermott, M. 1976. Chrysotile'induced asbestosis: Changes in the free cell population, pulmonary surfactant and whole lung tissue of rau. Br } Exp Pathol 57: 505-14. 10. Bradbury, P.,and Gordon, K. 1977. Connective tissue and stains. In Theory and Practice of Histological Techniques, J. D. Bancroft and A. Stevens, eds., p. 104. Edinburgh, Lon don, and New York: Churchill-Livingstone. 11. Gordon, H., and Sweets, H. H. 1936. A simple method for the silver impregnation of reticulin. Am / Pathol 12: 545-51. 12. Wilson, N. 1979. A method for staining polyvinyl chlorine in sections using Sudan IV. Stain Techno! 54: 101-02. 13. Richards, R.George, G.; Hunt, J.; and Tetley, T. D. 1980. Relationship between the hemolytic potential of certain par ticulates and their reactivity at the lung surface in vivo. In The in vitro Effects of Mineral Dusts, R. C. Brown, M. Chamberlain, R. Davies, and I. P. Gormley, eds., p. 323-332. London: Academic Press. URL 12283 INDUSTRIAL HYGIENE SAMPLING STRATEGIES (NIOSH 553), sponsored by die Midwest Center for Occu pational Health and Safety, will be held on April 22*24, 1981, at St. Louis, Missouri. The course content includes introduction to statistical sampling strategies, legal aspects of sampling strategies, fundamentals of statistics, estima tion and decision I and II, exposure measurement sampling strategies, compliance vs. non-compliance, full period sam pling, grab sampling decisions, ceiling limit sampling, com pliance officer sampler strategies, and statistical workshops. Industrial hygienists and supervisors who are responsible for sampling industrial atmospheres, making decisions on such sample results and taking appropriate action in com pliance with OSHA regulations should plan to attend. Three points will be awarded toward maintenance of certification from ABIH. CEUs will also be awarded. There is a fee of $375.00. For further information, write or call Ruth K. McIntyre, Director, Continuing Education, Midwest Center for Occupational Health and Safety, 640 Jackson Street, St. Paul, Minnesota, (612) 221-3771. January/February 1981 (Vl. 36, No. 1) 19