Document RJej5NDGmv98p2J4dBn5Z4E27

RESEwfionxiOPMENT MAR Z7T979 W. M. SMITH Mortality Experience of Workers in a Vinyl Chloride Monomer Production Plant Patricia A. Buffler, Ph.D.; Susan Wood, M.A.; Clayton Eifler, PhJO.; Lucina Suarez, M.S.; and Duane ). Kilian, M.D. The evidence associating exposure to vinyl chloride with the risk of tumors of various sites, including lung cancer, & inconsistent. In 7 976 a mortality follow-up study of 46f white males employed in a vinyl chloride monomer (VCM) production plant since 1948 was conducted. Vital status was ascertained for 100% of the cohort. Eight (28.5%) of the 28 deaths observed were due to malignant neoplasms. No angiosarcomas or other liver tumors were observed. A statistically significant excess was noted hr malignant neoplasms of the respiratory system (p--.03). The effect of smoking, duration of exposure to VCM, level of exposure, and the combined effect of duration and level of exposure were analyzed separately. A five-year latency requirement was maintained for alt analyses except for the smoking analysis. Levels of exposure to VCM prior to 7977 were estimated from monitoring data available for the period 1971-75 by extrapolating the relative levels for job classifications backwards in time. Smoking histories were not available hr 27.6% of the cohort. When it was as sumed that all "unknowns"smoked, a significant excess of respiratory cancer was stiil observed (p^jOS). When the minimum latency period of five years restricted analysis to fhemorta/rty experience after five years from date of initial exposure to VCM for the 314 employees satisfying this cri terion, the excess of respiratory cancer was moderate but not significant (p--.06). Both a longer duration and a higher level of exposure during the first five years following the date of initial exposure were associated with a statistically significant excess of respiratory cancer(p =*.02 andp--.03, respect/ve/yj. However, when duration and level of exposure were combined In an overall exposure index, the resuits were not significant (p--.07) The discrepancy in the results from the dose-response analyses may be due to the from th* University oi Tern Sthool ol Public Hctlih, PO On* 20166. HouKOn. tX 2702$ (Or. buffler And Mi Wood Swnii'tl Department of Preventive Medion* end Community Heilih, University of Tesii Mi-dicel Drench. CiKtMon. TX 77S50 (Or t ifleiI. inti Occupatiunai Heelth jnd Wedieel Ke\e*uR Dow Chnrmr.il Company. Freeport. TX 77541 (Dr Kitian) potential error in die estimated levels and the small number of events observed, but the results dofliggest that a relationship exists between exposure to VCM and respiratory cancer. I he association of vinyl chloride and the development of angiosarcoma of the liver has been well documented. Vinyl chloride has also been described as a multi-system carcinogen causing tumors in the lung, cen tral nervous system, and hematopoietic systems ''V Most recently it has been suggested that vinyl chloride is a chemical mutagen and teratogen.' Early in 1974, three cases of angiosarcoma of the liver, an extremely rare tumor, were reported among worke:s in a vinyl chloride polymerization plant.4 All three workers had at one time been involved in the manual cleaning of polymerization reactors/ In a recent report from Canada, this pattern was confirmed in 10 cases of angiosarcoma of tire liver.' Seven of the workers cleaned reactors, and the rest were either operators or maintenance personnel. In itial exposures for ail cases occurred before 1962. Following early reports, several epidemiologic studios of workers exposed lo vinyl chloride were initiated. The first of these investigations was a proportionate mortality study by Monson and Peters.'. The study involved 161 deaths from two vinyl chloride plants: a plant producing vinyl chloride monomer (VCM), and the polymerization plant where the initial cases of angiosarcoma were iden tified. The deaths, which occurred between 1947 and 1974 among active and retired employees, were analyzed for excesses in cancer mortality. Monson and Peters reported a 50% excess in the proportion of deaths due lo ail malig nant neoplasms. Specific excesses were found for liver and biliary tract, lung and brain. These results suggested that vinyl chloride may be a multi-system carcinogen, although the excesses reported were based on propor- Journal of Occupational Medicine/Voi. 21, No. 3/Ma195 AP00007374 donate mortality ratios, which arc not specifically a polymer plant workers, and monomer plant workers. The measure of risk. authors observed no relationship between length of ex In 1974, Tubershow end 061(07' published results uf posure and risk of cancer. This particular analysis, an industry-wide historical prospective study of 8,384 however, has been challenged as methodologically inap workers involved in the manufacture of vinyl chloride and propriate due to the misallocation of person-years.1' vinyl chloride polymers in 33 plants. The study was In 1975, the National Institute for Occupational Safety restricted to individuals who had at least one year of ex* and Health reported results from a follow-up study of posure to vinyl chloride before December 31. 1972. Ex 1.294 workers at four polymerization plants, two of which cesses for. the specific causes of death were not statisti also produced vinyl chloride monomer.' All workers in cally significant, except for cancer of the digestive cluded in the study had been exposed for five or more system, consisting primarily of previously identified years with at least ten years' latency period (ten years angiosarcomas of the liver, ihe excesses for cancers of since initial exposure) Significant risks for cancer of the the respiratory system and lymphomas, while not liver, lung, brain and central nervous system were found statistically significant were suggestive of possible risks for workers with 15 years of latency. An increased risk which appeared to be related to the dose of vinyl was also observed for lymphatic and hematopoietic chloride. Dose was measured by an average monthly ex cancers. posure score determined for each worker and based on a By contrast, the study reported by Few and Collier11 of subjective estimate of relative levels of exposure for jobs 7.000 workers ex(X>sed to vinyl chloride in the British in within each plant. The authors quite correctly point out dustry did not indicate that cancers other than those of that exposure levels between plants may not have been the liver were associated with exposure to vinyl chloride comparable. In addition, the inclusion of many workers monomer. In this study initial exposures for a fairly high with inadequate latency periods, some as short as one proportion of the workers occurred after I960, and year, may have obscured the exposure effects. This study follow-up by three of the eight factories was poor. In addi- . had been.extended to more adequately evaluate latency - tion. the-determination and analysis'of exposure were and to include more complete information regarding the questionable in that a measure of level of exposure ascer study cohort.* The final report is therefore based upon a tained retrospectively and subjectively bv the par total group of 10,173 employees from 37 plants, of whom ticipating industries was used rather than duration of ex 9j677 (95.1 %) were successfully traced. While there were posure, some combination of level and duration, or no statistically significant excesses of site specific specific job classifications. malignancies except for fiver (angiosarcoma) and brain, Some background information on vinylrdene chloride the risk of malignant neoplasms of the respiratory system (VOC), a structurally similar chlorinated hydrocarbon, is does appear to be associated with intensity of exposure-- also important In this review since exposures to VDC at a standardized mortality ratio of 92 for the low intensity lower concentrations often occur simultaneously in the category compared to that of 141 for the high intensity VCM production area studied. VDC Is a known licpalo- category. toxin" and has been recently described as a genetically In a study presented at the New York Academy of active compound in the bacterial test systems used.'* '* Science conference on vinyl chloride, Nicholson et ai1 The literature contains only one reporton the health and described an excess in total mortality and in overall mortality experience of workers exposed to VDC without cancer mortality among 257 men with five or more years simultaneous exposure to vinyl chloride.*' In this study of of exposure occurring before 1963 in a polymerization 138 workers, Ott et al" reported no excess mortality due plant. In addition, they reported three deaths due to an to malignant neoplasms or adverse health effects at giosarcoma of the liver, one due to cancer of the brain, tributable to exposure to vinylidene chloride. two due to lymphoma and none due to lung cancer. Based upon this review of the literature, the evidence Two additional mortality studies'* " resulted in essen associating vinyl chloride with the risk of tumors at tially negatne results. One of these, a mortality follow-up. various sites is strongly suggestive. However, some study of 594 employees at Ihe Dow Chemical Company results, particularly those reported for lung cancer, arc in polymer plant In Midland. Michigan, by Ott et al,'* re- consistent, and several questions remain regarding the yealed excesses in overall cancer only in the high ex strength of the association and the effects of varying posure category{> 220 ppm). In this study, evaluation of levels of exposure. The present study was undertaken to the effects of vinyl chloride was confounded by the fact further delineate the carcinogenic risk associated with ex that 72 of the 594 employees had also been exposed to posure to vinyl chloride by utilizing more definitive infor arsenic, a known carcinogen affecting the respiratory mation regarding duration and level of exposure, to system. Analysis fthe mortality experience among the evaluate the effects at lower doses, and to address some cohort without the aresnic exposed workers indicated a of t!w methodological problems found in other statistically significant increase in mortality due to malig studies.'* ** ** Although it would be desirable lo evaluate nant neoplasms, particularly lung cancer, among workers the specific effects of vinylidene chloride in the popula exposed to levels of vinyl chloride above 220 ppm. tion studied, unfortunately, it is not possible to separate Duck et al" found no significant excesses in overall or Its effects from those of vinyl chloride. cause specific mortality in a British-Petroleum chemical industry population of 2,120 male workers exposed to Materials and Methods vinyl chloride. The analysis included a separate evalua Subjects of this investigation were persons employed in tion of mortality for autoclave workers (reactor cleaners), a vinyl chloride monomer production plant of the Dow 198 Mortality Experience In a VCM Production Planl/Bulller et at AP00007375 Chemical Company. The facility began operations in 1948 when * smatt area of the chemical plant was dedicated to this operation and to the simultaneous production of vinyGdene chloride. The criterion for inclusion in the study was that an employee had worked at least hvo con secutive months in the vinyl chloride department be tween August 1,1948, and September 25,1975. Company personnel rosters were used to enumerate the cohort of persons who had worked in the department since 1948. Company records were utilized to compile in formation on date of birth, race, sex. and inclusive dates for each job and departmental assignment during employment. The vital status of employees who had left the company was determined by standard follow-up techniques. Death certificates were requested for all deceased employees, the certificates were coded according to the 8th Revision of the ICDA and reviewed by a nosotogist provided by the Environmental Epidemiology Branch of the National Cancer Institute. Pathologic or clinical infor mation was requested from the attending physician or hospital named on the death certificate for all cancer deaths. Clinical and pathology reports received were reviewed by the UTMS Pathology Department. Personnel monitoring data at the plant since 1971 and information from the Department of Industrial Hygiene and plant, supervisors . allowed. the. grouping .of ..all classifications with respect to potential exposure to vinyl chloride. Seven fob classification groups with similar potential for exposure within each group were identified. An industrial hygienist and a panel of five persons who had Jong-term experience with the production process and job assignments ranked the seven categories in terms of potential for exposure to vinyl chloride during the periods 1948-70 and 1971-75. The categories were listed randomly and each member of the panel independently ranked the seven groups. The rankings were consistent from one time period to the other, suggesting that although actual levels of exposure may have changed over time, relative levels had not and the recent monitor ing data could be extrapolated backwards in time. job classifications considered to have a relatively high potential for exposure included control lab personnel, loaders, and production personnel (control operators). A control lab worker sampled the product at several stages during the production process and analyzed it for purity. Much of this sampling is now automated. In earlier years K was common for the control lab worker to deliberately, but briefly, expose himself to vapors by methods such as the "sniff" test for sample purity, thereby incurring very high short-term exposures. Loaders are exposed to vinyl chloride in the process of connecting or disconnecting pipelines to tank cars and tank trucks. The control operators are responsible for monitoring the production process, performing minor maintenance procedures in order to insure proper functioning of equipment, and preparing equipment for major repairs. Maintenance workers generally have lower eight-hour lime weighted average exposures than do the control operators, but they often experience relatively high short-term exposures to vinyi chloride while repairing worn equipment. Employees with Use lowest exposures are those in super Tablet 1, -- Follow-up Status cf 464 Workers in a VCM Production Plant, August 1, 1948 September 25,1975. Still employed at company No longer employed. Hive Retired Released Deceased Died white employed Died alter (eaving company Died while retired Unknown status Total 291 US 27 ltd 28 17 It 0 0 464 visory positions followed by persons in the development lab. The assignments of supervisory personnel are such that they are not required to spend extended periods of time in the production area or to be physically close to the source of vapor emissions. Development lab person nel usually work with small quantities of vinyl chloride in evaluating the product or production process. The time weighted average exposures to vinyl chloride by job classification, based upon available monitoring data, were averaged for the period 1971-75 and are summa rized in Appendix A. Standardized mortality ratios (S.MR's) were computed in the analysis of the mortality experience of the cohort. Expected numbers of deaths for the study population' were calculated by.applying 195059 and 190069 agecause specific death rates for white males in Texas to the observed distribution of person-years of observation, categorized into five-year age groups. Significance testing is based on the assumption of a Poisson distribution for the observed number of deaths, utilizing a one-sided test of significance. In the analysis of the data, the effect of smoking, duration of exposure, level of exposure and the combined effect of duration and level of exposure were each considered separately, although a five-year latency requirement was maintained for all analyses except that of the effect of smoking. Results Four hundred eighlyone males were identified for in-' elusion in the study population. Evaluation of mortality risks was restricted to white males due to the small number of nonwhite males (17) in the cohort. The as certainment of vital status for the 464 white males as of the cutoff date was 10096 complete, and is described in Table 1. Follow-up investigation was required for 129 in dividuals who were no longer employed. Eleven of the total 28 deaths occurred among this group of 129 workers. Table 2 shows the distribution of the 26 deaths by underlying cause. Eight deaths (28.5%) were due to malig- Table 2. -- Distribution of 26 Deaths Observed Among Workers in a VCM Production Plant by Cause of Death. Causes el Death (ICDA 8th Rtrisbn) Cancer (140-209) Heart (390-45B) Accident |8H0E9O9) Other (038 9. 330.4 and 513} Ail causes No. ef Death 6 10 7 3 28 Journalol Occupational Medicine/Vol. 21. Mo. 3/March 1979 197 AP06007376 Table 3. - Cese Summaries ol Eight Cancer Deaths Observed Among Workers In a VCM Production Plant. ataUibfCmi mwarn flJTfc filrfifon (CDft) Okie of Death Age at Deatos (Yean) Bata el Initial Exposure to VCM Age at In'rtiil Exposure (Years) interval from Dale at Initial Years Expostn* ta 01 VCM - Dale of Death Exposure (Years) Smoking Pathologic History Confirmation 1. Cancer o! lung (tfi2.11 4*21-74 60 11-15-48 34 2- fYKray carcinoma bap (162.1) 12-01-58 53 10-18-48 43 1. Cvdnoma ef tong 1*62.1) 5-21-73 58 8-31-51 33 4. Meefiar ccf catinoma (162.1) 11-14-71 52 MI-57 38 S. l&Egnant mediastinal tumor unclassified with generalized aebftas(t63.1) 1-28-63 21 1-15-62 20 6. Cviwu d 4-12-71 48 11-17-52 caba(1S3J) 7.CmiinnlE metot. r> lung & neck (140.9) 9-03-66 31 8-01-62 27 8. Metastatic squamous cell cancer. palate (145.1) 9-28-71 57 4-18-49 35 7.3 10.1 21.7 10.9 1.0 .6 4.1 6.0 25.4 10.2 21.8 14.8 ^ 1.0 184 4.1 22.4 Yes Yes - X-ray repcet presumptive Yes No reports available Yes No reports available Yes Yes *~ Biopsy link Yes - Autopsy Yes No -- Biopsy report not received Unk No reports available link Yes - Autopsy nant neoplasms, four of which were confirmed upon review of autopsy, biopsy or x-ray reports by the UTMB Pathology Department. Case summaries for the eight cancer deaths are shown in Table 3. No angiosarcomas or other Ever tumors were observed. The eight persons who efied of carver were initially exposed to vinyl chloride prior to19631 and the four with lung cancer, prior 101958. Length of exposure to vinyl chloride ranged from seven years to 22 years in the cases of lung cancer, and the Inter val from date of initial exposure to date of death ranged from 10 years to 25 vears- Six of the 28 deaths reported here, including two of the eight deaths due to malignant neoplasms (malignant teratoma and alveolar cell car- tinomal. occurred among a special subgroup of 165 woritera exposed t-" 1,4-dioxare. These data were reported fci an earlier mortality study of workers exposed to 1.4-dioxane.*' Table 4a shows the observed and expected numbers of deaths by cause. For overall mortality, the standardized mortality ratio was 11% lower than expected. The total number of observed Jeaths due to malignant neoplasms was not sfentfkantly different from the expected (8 ob served vs. 5.19 expected). There is, however, a statistically significant difference between observed and expected fc' malignant neoplasms of The respiratory system (5 vs. 1.73, P -03). ....... Effect of Smoking The excess In mortality due to respiratory cancer necessitates a consideration of the effect of smoking as an explanatory variable. Differential patterns of smoking among the vinyl chloride workers as compared to the Texas white male reference population might account for this excess. The case summaries indicate that four of the five workers who died of respiratory cancer had a history of smoking; the smoking status of the fifth worker is unknown (Table 3). In addition, smoking histories are not available for a large proportion (27.6%) of the 46-1 white males In the total cohort. Because of the missing data on smoking status, it is difficult to identify the effect that smoking patterns may have on the results obtained. The potential effect of smoking on the expected mor tality was examined, however, by noting the consequence of an assumed pattern of smoking for the "smoking unknown" category. Assuming the availability of standard age specific rates for the two smoking categories, the ex pected mortality, under the conservative assumption that all those in the "smoking unknown" category were actual ly smokers, was computed. Unfortunately, an appropriate standard set of age specific rates according to smoking status was not readily available, but a reasonable set of rates was constructed from available information. The construction of these .standard rates is described in Ap- febfe 4a. -- Observed sad Depicted Numbers el Deaths Among 464 White Hales In a VCM Production Plsnt, August 1, 1848 to September 25, 1975. Cause at Death Observed Expected SMR All causes Ah malignant neoplasms NSaDgroni neoplasms of toe respiratory system * 28 8 5 31.63 5.19 1.73 89 154 289* *p= .032, one-tailed test 198 fable 4b. -- Observed and Expected Numbers of Deaths Occurring Five cr More Years Past Initial Exposure Among 314 White Males in a VCM Production Plant Prior to September 25,1970. Cause ol Death ah causes Alt malignant neoplasms Malignant neoplasms ot the respiratory system *p=,06. one-laDed lest Observed 22 6 4 Expected 25.18 4.34 1.49 SMR 87 138 268* Mortality Experience in a VCM Production Piant/Bufller et at AP00007377 pendix B. Under the extreme assumption that all "unknowns'' actually smoked, (he expected number of respiratory cancer deaths for the 464 while males is 1.98. With five deads observed, this excess is of borderline significance (p = <05} Since it is extremely unlikely that alf persons in the "unknown" category smoked, smoking appears to be an unlikely explanation for the excess respiratory cancer mortality. Effect of Five-Year Latency The latency period for occupationally induced cancers may range from five to 20 years from the date of first ex posure. In the above mortality comparisons, the ex periences of all workers, regardless of the length of time elapsed since initial exposure, are included. This tech nique may mask the effects of exposure in that a suffi cient latency period may not have accrued prior to death or observation. When the SMR's in Table 4a were recalculated utilizing a minimum latency period of five yean from the date of initial exposure to vinyl chloride, the resulting SMR for malignant neoplasms for the 314 employees satisfying this criterion was slightly lower, 268 versus 269 (Table 4b). Effect of Duration of Exposure Fifty-four percent of the cohort had less than two years of exposure to vinyl chloride. The average length of time 'spent m a vinyl chloride area* for alt 464 workers was 4.6 years. The values ranged from a minimum of two months to maximum of 26.9 years. It is Important to determine whether increased dura tion of exposure is associated with higher mortality. When looking for such a relationship, bias may occur if the ex posure and observation periods overlap." Death may ter minate exposure prior to the satisfaction of some minimum exposure requirement, so that some deaths fall in the category of short duration of exposure, regardless of whether the death was causally related to the ex posure. In addition, a long duration of exposure implies a long latency period in which malignancies possibly due to other chemicals in the environment may be observed. These problems can be avoided by the following tech nique, which separates the exposure and observation periods. Duration of exposure during the first five years follow ing date of initial exposure was noted for each individual exposed prior to September 25.1970, counting only ex posures incurred prior to that date. Individuals surviving the first five years after the date of initial exposure were then classified into two groups according to duration of exposure in the first five years. The groups were divided at the median value for duration of exposure, 2.29 years. Persorvyears of observation and the expected numbers of deaths for the period following the first five years since date of initial exposure were then calculated for the two groups. This procedure removes observed and expected deaths occurring among workers before completion of the minimum five-year latency period. Fig 1 illustrates the determination of these intervals for three individuals. The results of this analysis are shown in Table 5. There is a statistically significant excess of deaths due to respiratory cancer in the longer exposure group (4 observed vs. 1,05 expected, p .023} Effect of level of Exposure In order to further explore the relationship between ex posure to vinyl chloride and cancer mortality, one can consider a second dimension of exposure; the estimated level of exposure, or concentration. As previously men tioned, levels of exposure to vinyl chloride in the popula tion studied have decreased substantially in recent years, but based upon subjective evidence, the relative poten tial for exposure has not changed extensively. Therefore, the time weighted averages of exposures to vinyl chloride for the period 1971-75 were extrapolated backward in time to obtain an estimate of minimum exposure levels for the various job categories. Average exposure indices were obtained for each individual for the five-year period following Initial exposure by multiplying the extrapolated exposure level for each job classification by the time spent in that job during the initial five-year period. These products were summed over all jobs in (he initial period, then divided by the total time exposed to vinyl chloride in this initial five-year period. Only exposures before September 25.1970 were counted, thereby allowing for a five-year latency period as defined above. Categories of high and low level exposure were defined by the median extrapolated level of exposure for the 314 individuals alivn and under observation at the end of the initial fiveyear period. The- mortality experience observed subse quent to the initial five years for the categories of high and low average levels of exposure is illustrated in Table CijMur* Siartif'q Colt Observation Cul off Date j August 1,1948 Jewy Sept 25. Stpt 2S' 1984 1970 1975 I _______________________________ _J____________1____________ ' Individual ;A Individual B V---------- *-------------- X * `--------* Iniliol 5 OMervolien perieo ; period ; Initial Syr, Otaervolion period period j { exposure no exposure Individual C !-------------- Initial $yc period ...... --i..... -- Fig 1. -- Example of determination of duration d exposure during live years following date of Initial exposure to vinyl chloride lor three employees exposed prior to date allowing for 5-year latency (September 25,1970). The initial date of exposure for Individual A was January 1, 18G4, prior to September 25,1970 (the eutotf dale minus 5 years). He tiled on January 1,197S. Since Individual A was continuously exposed tor the entire five-year interval from the dale of his initial exposure, the person-years of observation after January 1, 1969, and his death would be assigned to the long exposure category, > 2.29 years. By contrast, Individual 8 was exposed for only two years during the live-year interval from the date of his initial exposure, contributing approximately eight person-years to the short exposure category. Individual C represents an additional category of observations: those individuals for whom an initial live-year interval was not completed prior to September 25, 1970 (the study cutoff date minus 5 years) and were therefore excluded from these analyses. Journal of Occupational Medicine/Vol. 21. No. 3/Msrch 1979 199 AP00007378 Table S. -- Observed and Expected Deaths Among 314 White Male; In a VCM Pfoduefion Plant by Initial Five*Year Duration of Exposure.* Initial 5-Yc; Duration Dears) Short (< 2.73) long (>>.29) Na. tf Proeru .157 157 PersonYuri 1123 2227 Malignant Naotasms Ah Malignant of ihe M Csustt Neoplasms Respiratory System Cbj. Fxp. sue Ohs. Exp. SMR Ohs. ftp. SMR ? 7.7S 90 1 1.32 IS 17.43 66 5 3.02 76 0 166 4 .45 0 1.05 38Vf * fpr 314 Indwtduilj exposed belore Sepamber 3$. 1970 end exposures incurred before lhat dale, counting deaths occurring live or mors years after initial exposure f p - .023, one tailed test 6. Again, there u a statistically significant excess of respiratory cancer in the group with a high average level of exposure (3 deaths observed vs. .68 expected, p * .0321 Effect of Duration and Level of Exposure Finally, a dose-response analysis was carried out for a cumulative exposure index of information regarding both duration and level of exposure. This index, for a given in dividual and period of exposure, is the product of the duration of the period of exposure and the time weighted average level as previously defined. The mortality ex perience occurring five years after initial exposure for in dex groups of high and low level exposures, as defined on the basis of the first five years from initial exposure, is given in Table 7. The excess in the high level exposure group is not statistically significant (p = .07). died before termination, they would have been included in the study. Removing from the analysis those persons who terminated employment creates a tendency to overestimate the 5MR. as noted in Table 8. A second potential source of bias in the analysis with limited follow-up Stems from the possibility that persons ter minating employment before retirement may difi'er in cer tain demographic or environmental characteristics related to n ortality. Lastly, the elimination of a signifi cant number of individuals from the study reduces the precision of the estimate of the $MR. This is particularly undesirable when small numbers of deaths are involved. Despite these problems, it is not uncommon to find this type of limited follow-up analysis in the literature. To avoid the various sources of error in this type of analysis, it is preferable to strive for a complete cohort, as was done in this study. Results With limited Follow-up It is of methodologic importance to the evaluation of results from studies with incomplete follow-up, as well as to the conduct of future studies, to compare ihe results obtained with complete follow-up to those obtained with limited follow-up, that is, by "standard" techniques utiliz ing individuals who are easy to locate (current employees and retirees, and deaths occurring in these two groups on ly! Table 8 shows that the results with limited and with complete followup are similar when comparing overall mortality between the two groups, but that results differ somewhat when comparing mortality due to malignant neoplasms, specifically malighant neoplasms of the respiratory system. There are several sources of error in herent in the SMR's reported with limited follow-up. First of all, individuals removed from the analysis were certain to have survived up to their termination date. If they had Discussion One of the most challenging problems in a cohort study of the type presented here is the delineation of ex posure. Although no historical documentation of ex posure to vinyl chloride exists prior to 1070, it was reported that during the early period of production (1948-1960), exposures in the range of several hundred ppm (200-500 ppm) were not uncommon. During the 1950's and early 1960's the standard for exposure to vinyl chloride (threshold limit value, TLV) was 500 ppm.'* In 1961, based on chronic toxicity testing, the Dow Chemical Company voluntarily reduced their exposure standard to a TWA of 50 ppm (100 ppm ceiling).** In 1974 the perma nent OSHA standard for exposure to vinyl chloride was reduced from 50 ppm to 1 ppm for an eight-hour period.** As previously rioted, workers in the cohort under study were simultaneously exposed to VCM vapors and varying TajrJe 6. -- Observed end Expected Deaths Among 314 White Males in a VCM ^ Production Plant by Estimated Relative Level ot Exposure lor Initial Five-Yeer Exposure Interval* Avg. Level at Exposure During Intel S Years) 1(o. d Persons TenonYears Obi. All Causes ftp. SMR AH Malignant Neoplasms Ob*. ftp. SMR Malignant Neoplasms f the Respiratory System Obj. ftp. $Mft low 160 1374 10 13.56 74 2 2.38 84 1 42 122 High 154 1977 12 11.62 103 4 1.95 205 3 .68 441* * For 314 indivftjiiats exposed before September 25. 1970. exposures incurred during the five-year interval from date of Initial exposure, and counting deaths occurring five or more years after initial exposure f Based on 1971-75 monitoring data j p= .032, ate-uited ten 200 Mortality Experience in a VCM Production Planl/Bulller et at AP6o607379 Table 7. -- Observed and Expected Deaths Among 314 While Males in a VCM Production plant by Exposure index for tnfttaf ffw-Year Exposure Interval.* Initial S-Ynr Exposure ledext Low Hlah Ho. of Persons 157 157 PerronYears 1143 2207 Malignant Neoplasms AD Malignant 1 the A Causes Neoplasms ftttpbttvy System Obs. Exp. SMR Obs. Exp. smr Obs. Exp. SMR 9 9.40 95 3 1.62 1S5 1 .56 ISO 13 15.79 82 3 272 110 3 .94 3191 For 3M individuals exposed before September 25. 1970. exposures incurred during (he five-year interval from date ot initial exposure, and counting deaths occurring fixe or more yeara after initial exposure t Cased on 1971-75 nmocnag data tpsj)7. one-uBed lest concentrations of vapors from the production of VDC, ethylene dichloride, methyl chloroform and ethyl chloride. A weaknes: of most mortality studies of chemical indbtry employees is that workers may have been exposed to many other chemicals while working in other areas of die production facHity or in other chemical companies before or after the period of specific observa* tion-We were able to determine that no members of the cohort had been exposed to arsenic or asbestos while they were employed at the Dow Chemical Company. In view of the lack of data regarding levels of exposure prior to 1971, an assumption was made that while levels of exposure were higher before 1971, the ratios of levels for any two job classifications remained approximately constant. It is believed that reasonable estimates of the relative levels of exposure prior to 1971 were made by backwards extrapolation of post-1971 exposure data. It is also important to note that initial exposure to vinyl chloride occurred in mid-career (34-43 years of age) for all four persons who died of lung cancer [Table 3). In this regard, the lack of information on previous employment or occupational exposures for these individuals adds to the difficulty' of interpreting the significance of these statistical findings. To pursue the question of whether this excess may be causally related to VC exposure, a dose-response relation ship was examined. Dose was considered to have two dimensions, duration and level of exposure. In testing for a dose-response relationship, a comparison of mortality may be biased If the periods of exposure and observation overlap. We avoided this source of bias by looking at an initial five-year exposure period and a subsequent obser vation period, thereby also allowing for a five-year laten cy period past initial exposure. With regard to duration of exposure m the first five years following initial exposure, there was a statistically significant excess of respiratory cancer occurring after the initial five-year period (4 versus 1.0S expected, p .02) among workers in the longer ex posure group. No such excess was observed for workers in the shorter exposure group. In the three analyses of-dose-response performed In this study, the most accurate and objective measure of dose available is duration of exposure, which ignores the concentration component of dose. On the other hand, the cumulative index takes into account both duration and level. Is based on data extrapolated into the past, and assumes that the relative levels of exposure did not change over time. If thi,$ assumption were false, any ex isting dose-response relationship would be obscured, had the true cumulative indices been known. The use of the time weighted average levels as a measure of dose is not so heavjjy dependent on this assumption. Possible ex planations for the fact that statistical significance was observed in two f these analyses, but not the levelduration Index, may be due to the potential cror in the .estimated, levels, and in the small numbers of events observed. It should be mentioned that our inability to detect an increase in mortality in the low level exposure groups does net necessarily indicate that no increase ex ists, but may be due to the low power associated with small expected numbers, and a longer latency period at lower doses. A more appropriate statistical technique for these types of dose-response analyses might be a comparison of the increase in the high level (or long) exposure group to that in the low level (or short) exposure group. Statistical inference on the ratio of the true underlying SMR's for the two exposure groups can be carried out conditional on the number of deaths in the two groups combined.17 However, when die numbers of deaths are small, the power of such a comparison is very low, and may even be zero. Because of this inefficiency, it was deemed ap propriate not to report significance levels, but rather to note that although statistical significance was not ob served, the probability of observing such was very low. Throughout this study, as is common in occupational studies, the measure of mortality used is the SMR, There are, however, several problems with the use of SMR's that should be kept in mind when interpreting such results, -especially when comparisons of SMR's are made. Limited tottow-up Compile lohow-up Table 8. -- Observed and Expected Deaths Among White Mates to a VCM Production Plant by Type of Follow-Up. Ne. el Persons 335 464 PersonYears 3067 5313 Overall MiBgnanl Malignant Neoplasms MortsEty Neoplasms of the Respiratory System Obs. Exp. SMR Obi. Exp. SMR Obs. Exp. SMR 13 20.55 88 5 343 175 5 1.16 431* 29 31.63 89 8 5.19 154 5 1.73 289t p=.007. one-ttfcd test 1 pe .032 Journal of Occupational Medicine/Vot. 21. No. 3/March 1979 201 AP00007380 Although (he SMR is an adequate measure of excess mor tality as compared to the mortality of a standard popula tion; the comparison of two SMK's depends not only on he differences in the aye specific mortality rales of each group from the standard, but also on the age specific population weightings of the two groups. Thus, it is entire ly posslsle. if the age distributions are vastly different, that (he two study groups might have equal age specific mortality rates but somewhat different SMR's. Despite die problems m the use of SMR's. no alternative was con sidered because of the small numbers involved. Conclusions fn view of our inability to detect a significant dose- response relationship, we cannot state that the observed excess In respiratory cancer deaths is due to exposure to Vyf chloride. However, the fact that excesses were seen fci tiie group with the longer duration of exposure in the initial five yca/s, and rn the group with the higher average estimated exposure levels in the initial five years, suggests that a relationship may exist. It is unfortunate that data were not available regarding the levels of exposure experienced 20 to 30 years ago, when ihe four workers with respiratory cancer were first exposed to vinyl chloride. It is also unfortunate that data were not available regarding exposures to other chemicals during these earlier decades, The results of this study can only be considered in con junction with other studies, both past and future. In view of wagisteit reports.to date, more studies of the specific dose relationships and confounding exposures are needed. this study was kindl'd by a fdearth etvjrd from Dow Chemical Co. U S A The tuition wnh to aefcno-lu(l|ic thr support and oisutAntc ot (ho v.miOu) Deportments of Du* CheiriKal Co. Tei Division and USA, without when) this study could n<it have tern condurwd the Oetupji.vnjl Health and Mnhcjl Inuik Dvpmneac. tndmlfiat Hygiene Department. Ihe In^^iil iitfct Department Mid the Personnel Department The critical Kin erf 0m novt by Dr Bolph Cook. Do Chemical Co. USA end (he enirtrnre Mrdu! by iheUlXIB Putholoyv Depaitmeni. |lu Umve/iit\ ot Ttui f Houston education end Research Comnutnitors Center, end the f n vifonmental f pidemiolog^ Branch of the Nationjl Center Cenu-r m v\u`v.>ng and processing date h acknowledged This |mprr was wsut-il as Cut Du* Technical Release 8600-407-76. References t. Mcohk It* and fWen JM: Propertmnat mortality among vinyl cftfaridV wtstlen lancet 2J97O90.1974. 2. Taboohaw IR and CafTey WR. Mortality study of workers in the manufacture of vinyl chloride and its polymers. J Occup Med 16 509516. 1974. X Kichelson \VJ. ifarvnon IC, Sekiman H. and Selikoff il Mortality evuerienee of a cohort of vinyl dsloride-polyvinvl chloride workers. Arm NYAearfScf *46.225230, WS. ~ 4. Wavwefcr RJ, Stringer W, Wagoner IK. and Jones J Neoptatic risk among workers exposed to vinyl chloride. Am NY Acid Sc* 2714046. 1976. 5. Infante P. Wagoner |K, McMicturf AJ, et al. Genetic risks of vinyl chloride. Lancet 1:724-735, VJ76. 6. Cicech IL a:id Johnson MM. Angiosarcoma of liver in the manufaehae ot polyvinyl chloride. J Occup Mud 16.150-151.1974 7. Block J: Anpetaacem* of the ktt following vinyl chloride exposure fAMA 2295254, m 8 Oetocme f andTheriault C: Ten cases of angiosarcoma of the liver In Shawinfean, Quehec. / Occup Med 20.3SM1Q,-1978 9 Equitable Environmental Health. Inc; Epidemiologic study of vinyl chloride workers: Final report submitted to Manufuctsemg Chemist* Association, January, 1970. 202 10 OU MG. lanfiner RR, and Hulck-r 86. Vinyl thloridu (T*|vj't.'re in a controlled industrial enviroiimmt Arch Fniiton Health 30 3 J3-1 ft. 1975, 11 Ouck BW. Cart* JT.and Coobet tj. Mortality study of woilwj in a poh vinytchloralv pciduftion plant lancet 21197-1199, 1975 12. Wocoru.i |K and Infante I'K Vinyl chloride and mortality? letters to the Editor. lancet 2194-195.1976. U. To< A) and Collier Pf; Mortality cx-penence of workers esposed to vinyl chloride monomer in thy maiuriaciu.-o of polyvinyl chloride1 in Cre.it Britain Be t M Mod 34.1-10.1977. 14 Jenkins LJ, 1r.ibukrs MJ, and Murphy SO. Oioctwmieaf effects of l.ldichloroeihvtene in rats: Comparison with earixm ivtiachluriric and 1. 2-dicMoroethylcne. Toxicol Appl Hha/macol 23 SOI -510,1972. 15. McCann J, Choi E. Yamasaki l, and Ames DM, Oetectioi- of car'Chsogfns as mutagens the Salmonella,hticrosome test Assay of 300 chemicals. Proc Nad Arad Sci 72 5133-5139.1975. 16. B.irttch H, Malavcille C. Mcniesano R, and Tomaiis l: 1 issue mediated mutagenicity of vinylidene chloride and 2-chtorobuUd>cuc in S. Typhimurium Nature 255.641-653. *1975 '17. Oct MG, Fbhbeck WA. Townsend MS, and Schneider FJ. A health study of employees exposed to vinvlidcne chloride. / Occup Mcrf 18:735-736.1976. 18. Pasternak BS and Shore KE: Statistical methods of .issesdng risk following exposure to environmental carcinogens, in Environmental Health: Quantitative Methods, A. Whitlcmore (Ed.) Philadelphia: Society for Industrial and Applied Mathematics. 1977, pp 49-71 19. liddei! TDK, McOonald IC <nd Thomas DC: Methods of cohort analysis. Appraisal by application to asbestos mining / Royal Star Soc 140469491.1977, 20. Enterline Pc: Pitfalls in epidemiological research. / Occvp Med 16:150-156.1976. 21. Ouffler PA. Wood SM, Sujrw I., and Kiffan Of: Mortality followup of svakns exposed to 1,4dwxane, / Occup Med 20253-259,1978 22. Kahn HA: The Dorn Study of smoking and mortality among US. veterans: Report on eiglvt and onehalf years of observation National Cancer Institute Monograph No. 19.1-125. U.S. Dejurtmunl of Health, Educatioa and Welfare. January 1966 23. US Departnx-nt of HtVV: Changes in cigarette smoking hjbi'S be tween 1955 and 1966. Public Health Service Publication No. V.OQ, Senes 10, No. 59. U.S Covemnwnt Printing Office. Washington. D.C. 24. ACCIH: Threshold limit values lor I960. AMA Arch fmirn Health 1 62.1960. 25. Torkclson 1R. Oyvn F. and Rowe VK: The toxicity of vine I chloride as determined by repealed exposure of laboratory animals Am ind tiyg Assoc J 22.354061. 1961. 26. Department of labor. Occupational Safety and Health Administratbn: Exposure of vinyl chloride, federal RegMet 39.35tfJQ-35693, Part l|, October 4.1974. 27. Edoror F and Mantel N: Confidence limits on the ratio ol nvo Poisson variables. Am / Cpidembl 190165-167,1974. Appendix A Estimated Time Weighted Average (8-Hour) Exposure to Vinyl Chloride by /ob Classification, 1971-1975 Percent of Total Job Classificatio:i Average Person-Years 8-Hr. TWA -Exposed 1. Control lab personnel 22.3 2. Development lab personnel 4.1 47 5.7 5. Production personnel Control A Control B Control C Class 3 operators Total 4. Loaders and plant men 7.7 16.6 28 7.5 4,4 8.9 -- .8 5,7 33.8 Class 1,2 operators Head packaging operator Material handling 7.1 12.3 152 U operator .2 .1 Mortality Experience in * VCM Pioduction Plani/Buliiei et al AP00007381 Packaging operator. service technician Total 5. Certain supervisory positions Production super intendent, assistant production superinlendent, production engi neer, R&D engineer, engineer, safety engi neer, Sr. production engineer, Parts technician, Sr. Manager Assistant engineering technician General superintendent, section superinten dent, superintendent, supervisor, assistant superintendent, plan ning engineer, material control clerk, plant assistant, head clerk, .. chief material handling technician, shipping coordinator,mainte nance coordinator, maintenance engineer Total laintenan.ee personnel Boilermaker, apprentice Welder, apprentice Machinist, apprentice. helper, crew leader Pipefittw, apprentice. helper Utility man Instrument technician Production foreman, shift foreman Maintenance foreman Utility crew leader, rotating shift foreman. foreman Total --* 7.4 1.9 2 3 JO -- 16 1.4 2 1.1 17 32 43 .4 -- 25 .1 16.4 93 .1 2 JO 1.9 11.6 1.2 1.1 17 43 1.2 37 55 2 52 240 7. Other personnel Electrician, apprentice Loading supervisor, technical foreman, coverer, janitor, elec trical foreman Total All groups combined 3.8 5.4 20 1.8 3.8 100.0 far lorne jobctoisificitiOM tSjt# wre no montains cbt* ambbl* fur ilw intervet 1971'75 The value turned di'lerrnvied by aver<i;*,l *3 mo'vionnj data frtfcbte for iob eiu3atrDM within the ftoop te wtrnh the ttxeific job cl.mthcabun wu >cned The average} computed were we^hbrd according to loul peopnyears in the cohort spent in each |ob claurfictlion Appendix B Despite the lack of suitable standard age specific rates for smokers (present or past) and nonsmokers (never smoked), it is possible to construct a reasonable set of rates from available information. The following two simplifying assumptions are made: 1. Age specific relative risks for smokers compared to non smokers from the study by Dorn*' for U S. while male veterans for the years 1954 o 1962, are applicable to the Texas white male populations of 1950-59 and of 1960-69. 2. The age specific percentages of smokers for U.S. males for the years 1955 and 1966,,-refiect-the correspon ding percentages for the Texas white male population in the time periods 1950-59 and 196069, respectively. Using these two assumptions, a set of age specific rales for the Texas white male population according to smok ing status was constructed for use as a standard, in the following manner. Let Mi-- cause specific mortality rate for age group i M= cause specific mortality rate for smokers in age group i M= cause specific mortality rate for nonsmokers in age group i $i-- proportion of population in age group I who smoke n-- age specific relative risk for smokers com pared to nonsmokers Then Mi sM. + C1-S-) M = Mi(s.r. + (1 - s.)] = M./[st, + d-sOJ: Mu = rm. Thus, the values for r. and s(are found for assumptions 1 and 2 above, and the desired mortality rates by smoking status are obtained. Truth Truth rests on several conditions. Among other things, truth rests on a regard for relevant facts, an Intelligent assembling of them and on knowing how the facts matter. Truth also rests on knowing what Is important and what is not, on Judgmental capacity and on courage. -- Itam -When Valuti err Substituted for Truth* by I lenm-u. in The Wufl Vri-i-l louirut. hity 21. 1978. Journal of Occupational Medicine/Vol. 21, No. 3/March 19/9 203 AP0bb07382 AP00007383 ! i l i i Table 3.2. HEALTH EFFECTS OF VINYL CHLORIDE: REVIEW CANCER Liver, and Hilary Cancers Angiosarcoma . Gallbladder Ca Adenocarcinoma of common bile duct Brain and CHS Cancer (Glioblastoma multiforme) Respiratory System Cancer (Large cell undifferentiated, adenocarcinoma) Lymphatic and Hematopoietic Other 1 Buccal, pharyngeal, lymphomq, digestive organs, thyroid a REFERENCE j| I \ Creech and Johnson (1974), Nicholson et al. (1975) Waxweiler et al. (1976) Waxweiler (1976) COMMENT US incidence: 0.014 cases per 100,000 pop. per year (Meath, 1975) Angiosarcoma also caused by ThOg* As, pesticides. (Van Duuren, 1975) Waxweiler (197/5), Infante (1976) Waxweiler (1976) Tabershaw and Gaffey (1974) Monson et al. (1974) Monson et al. (1974) Tabershaw and Gaffey (1974) These are not the types associated with smoking Not statistically significantly elevated among VC workers i i i Table 3.2 (continued). * HEALTH EFFECTS OF VINYL CHLORIDE: REFERENCE m! ; REVIEW COMMENT VINYL CHLORIDE DISEASE Nonspecific Svmptons Upper abdominal cramps, dizziness, headache, vision disturbances Lilis et al. (1975) Marsteller al al. (1975) j Makk et al. (1974) Hiller et al. (1975) Veltman et al. (1975) ( Extremities > Pain In joints and fingers * Acroosteolysls Raynaud's Syndromes Abnormal Allen Test Scleroderma-1ike skin changes Blood | Thrombocy topen1a Leukopenia t Clubbing of fingers, dissolution of terminal phalanges Coldness and pallor of the fingers Delayed arterial circulation of radial and ulnar arteries t i Liver , Hepatomegaly, splenomegaly i Chronic Hepatitis Hepatic capsular fibrosis i Degenerative alterations of liver cells, thought to be pre cursors of angiosarcoma ; ,. U J fj AP00007384 Table 3.2.(continued). HEALTH EFFECTS OF VINYL CHLORIDE: REVIEW li * Abnormal liver function tests (BSP (bromosulphalein) retention, SGOT, GGPT, SGPT, alkaline phosphatase, bi1irubin) REFERENCE Pulmonary Decreased air flow e.g., FEF25, FEVp HHF REPRODUCTIVE OUTCOMES Infante (1976) Increased total congenital IM* malformations ' . Esp. central nervous system defects, e.g., anencephaly, spina bifida, hydrocephalus CONDITIONS THAT HAVE BEEN EXAMINED, BUT NOT FOUND TO BE ASSOCIATED UITil VC Cardiovascular-renal deaths Abnormal urine analysis *fabershaw and Gaffey (1974) ii. Monson et al. (1974) Lilis et al. (1975) Cerebrovascular accidents Hypertension i i I1 Monson et al. (1974) I. Lilis et al. (1975) ]! :! : , it i i i COMMENT Also Influenced by smoking, possibly air pollution Community-based study, examining rates for towns with VC plants AP00007J85 EXHIBIT A SCOPE OK WORK The Contractor shall design, conduct, analyze, interpret, and report an epidemiologic study of the health effects of vinyl chloride is a population of children who were exposed to vinyl chloride. This study will involve the identification of a cohort of exposed persons, the location and contact of them, administration of interviews, maintenance of an up-to-date roster of the cohort, searching and retrieval of death and hospital records, and the estimation of vinyl chloride exposures. Throughout this study the Contractor shall follow sound quality control procedures, especially in regard to data collection and processing. 1. Phase 1 s. Task 1 - Identification of the Exposed Cohort Rotter The Contractor shall prepare n list of an exposed population at least a portion of which were initially exposed approximately 20 years ago to vinyl chloride.' This list shalL include as a minimum, full name, home address, telephone number, and dates of attendance. Furthermore, th?^ current address of each child shall be updated through the use of junior and senior high school records and other means if necessary. b. Task 2 - Preparation of Detailed Study Protocol Within 45 days of contract award, the Contractor shall submit to the project officer for approval a detailed study protocol which shall specify: (1) the procedures to be used in locating and contacting the population to be studied: 1,2} the precedures to be followed in deriving ."a *.-.* : r.y ` *'* L: ri f txr:-sures f: r the longest feasible stuiy peri:i. ar.i tie details c: tr.% exar.i&atitr. schedule, iuestionnai-rts, clinical, procedures, etc., to be administered to the participants of the pilot study. The detailed study protocol shall also specify what quality control procedures will be followed throughout the study. The Con tractor shall submit to the project officer all information as will facilitate the Office of Management and Budget clearance for the questionnaire. c.V% Task 3 - Preparation of Vinyl Chloride Exposure Estimates Upon approval by the project officer of the section of the detailed study protocol dealing with the generation of vinyl chloride exposure estimates, the Contractor shall: (l) collect and assemble the data necessary to generate the estimates {2) perforin the necessary calculations and (3) present the estimated annual exposures for the individual years during the*period of study. AP6b607386 Z8Z0000dV * ssTJsg ?:zodag xottjqoa ?tiaajt!oxaAag put qottasay jo aotjjg *tV<3 UT no?3fatxqnd joj axqtltns umoj c ut paqjodaj put pozZ^tut oq tltqs t?*p m -aansodxa aptjoiqo iZqxa pa?eui??sa Iraq? ;o sxstq aq? oo pai;??ti?s aq ^t.n s?uediOT?Jcd pn?s q?xq.n ut pn?s dTSotoiutapjda u aonpotd 03 uotqexndod ^eastiaS aq? uo t?*p q?itaq aiqtftiAt put \ qstj, jo s?-[nsa.T aq? q?tn pautqoioo aq uoq? xjtqs sa^TAr??* o.\oqe aq? uroj; u?tp aqx Xooo?jd pn?s pafre?ap aq? ut pat;roads sa.rnpaoo.id aaqio put a/tat.vzaqu't aq? lanpuoo [Itqs iQ?oe.t3UO0 aqx jaqoiotu ?joqoo Zpn?s ?ojtJ Tq*1*3I qata q?trt to^^^ojd Zpms pajxeiap aq? ut pat;toads sa saanpaoojd ?aq?a put s.naiAJotuT ajiipoqot xif,l* -to?3ej?uo3 aqx 'Jsotjjo toaCoid aq? q pdAOidde s tooojgjtd pn?s pan*?p aq? ut paijjjads sutfd aq? q?iA oouepjooof* ut. . j3?soj ?joqoo ainsodxa aq? jo s.iaquaw 0001 Zia?*utxo.idJa jo ajdaits t q??* ?ot?uoo a?t???u? ne,H Jo?at^?uoo oq? ?a8pny puc ?uawa8eu8j4 jo aotjJO rtq aJtPinjot?sonh aq? jo [uaojiMp u*>d,? 3aoqoj'"ijnsodj?3 >q? [o~<>'jTT^puf<1'?V:pn?5