Document DaeyRL1XQV1V1d6mKgYxmoBB

R&S 001470 smical Company. The facility began operations in 1948 fen a small area of the chemical plant was dedicated to ^operation and to the simultaneous production of lidene chloride. The criterion for inclusion in the tody was that an employee had worked at least two concutive months in the vinyl chloride department be en August 1, 1948, and September 25, 1975. J.Company personnel rosters were used to enumerate cohort of persons who had worked in the department Knee 1948. Company records were utilized to compile inMrmation on date of birth, race, sex, and inclusive dates forAeach job and departmental assignment during 5nployment. The vital status of employees who had left company was determined by standard follow-up chniques. I^Death certificates were requested for all deceased iployees. The certificates were coded according to the Rth Revision of the ICDA and reviewed by a nosologist jrovided by the Environmental Epidemiology Branch of i National Cancer Institute. Pathologic or clinical infor mation was requested from the attending physician or spital named on the death certificate for all cancer deaths. Clinical and pathology reports received were viewed by the UTMB Pathology Department. ^Personnel monitoring data at the plant since 1971 and |mormation from the Department of Industrial Hygiene lind plant supervisors allowed the grouping of all glassifications with respect to potential exposure to vinyl iJoride. Seven job classification groups with similar jjjfential for exposure within each group were identified. Industrial hygienist and a panel of five persons who long-term experience with the production process I job assignments ranked the seven categories in terms ^'potential for exposure to vinyl chloride during the eriods 1946-70 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 j?over time, relative levels had not and the recent monitorling 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 '-it 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 |kers generally have lower eight-hour time weighted rage exposures than do the control operators, but they often experience relatively high short-term exposures to vinyl chloride while repairing worn equipment. Employees with the lowest exposures are those in super Table 1. -- Follow-up Status of 464 Workers in a VCM Production Plant, August 1, 1948 - September 25, 1975. Still employed at company No longer employed, alive Retired Released Deceased Died while employed Died after leaving company Died while retired Unknown status Total 291 145 27 118 28 17 11 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 (SMR'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 1950-59 and 1960-69 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 eighty-one males were identified for in clusion 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 100% 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 28 deaths by underlying cause. Eight deaths (28.5%) were due to malig- Table 2. -- Distribution of 28 Deaths Observed Among Workers in a VCM Production Plant by Cause of Death. Causes of Death (ICOA 8th Revision) Cancer (140-209) Heart (390-458) Accident (E800-E999) Other (038 9. 330,4 ana 5131 All causes No. of Death 8 10 7 3 28 Journsi of Occupational Medicme/Vol 21. Mo. 3/March 1979 197 Table 3. -- Case Summaries of Eight Cancer Deaths Observed Among Workers in a VCM production Plant. Underlying Cause of Death (8th Revision ICDA) Date of Death Age at Deaths (Years) Date of Initial Exposure to VCM Age at Initial Exposure (Years) Years of VCM Exposure Interval from Date of Initial Exposure to Date of Death (Years) Smoking Pathologic History Confirmation 1. Cancer of lung (162.1) 4-21-74 60 11-15-48 2. Primary carcinoma lungs (162.1) 12-01-58 53 10-18-48 3. Carcinoma of lung (162.1) 4. Alveolar cell carcinoma (162.1) 5-21-73 11-14-71 58 52 8-31-51 2-11-57 5. Malignant mediastinal tumor unclassilied with generalized metastasis (163.1) 1-28-63 21 1-15-62 6. Carcinoma of colon (1S3.8) 4-12-71 48 11-17-52 7. Carcinoma of lip metas. to lung & neck (140.9) 9-03-66 31 8-01-62 8. Metastatic squamous cell cancer. palate (145.1) 9-28-71 57 4-18-49 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 liver tumors were observed. The eight persons who died of cancer were initially exposed to vinyl chloride prior to 1963, and the four with lung cancer, prior to 1958. 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 years. Six of the 28 deaths reported here, including two of the eight deaths due to malignant neoplasms (malignant teratoma and alveolar cell car cinoma), occurred among a special subgroup of 165 workers exposed to 1,4-dioxane. These data were reported in an earlier mortality study of workers exposed to 1,4-dioxane.11 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 deaths due to malignant neoplasms was not significantly different from the expected (8 ob served vs. 5.19 expected). There is. however, a statistically significant difference between observed and expected for malignant neoplasms of the respiratory system (5 vs. 1.73, p = .03). 34 7.3 25.4 Yes Yes -- X-ray report presumptive 43 10.1 10.2 Yes No reports available 36 21.7 21.8 Yes No reports available 38 10.9 14.8 Yes Yes -- Biopsy 20 1.0 1.0 link Yes -- Autopsy 29 .6 18.4 Yes No -- Biopsy report not received 27 4.1 4.1 Unk No reports available 35 6.0 22.4 Unk Yes -- Autopsy 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^ft this excess. The case summaries indicate that four of wP 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 464 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- Tabte 4a. -- Observed and Expected Numbers of Deaths Among 464 White Males in a VCM Production Plant, August 1, 1948 to September 25, 1975. Causa of Death Observed Expected SMR All causes Ail malignant neoplasms Malignant neoplasms of the respiratory system 28 31.63 89 8 5.19 154 5 1.73 ro tCoD p= 032. one-tailed test 198 Table 4b. -- Observed and Expected Numbers of Deaths Occurring Five or More Years Past Initial Exposure Among 314 White Males in a VCM Production Plant Prior to September 25, 1970. Cause ot Death All causes All malignant neoplasms Malignant neoplasms of the respiratory system Observed 22 6 4 Expected 25.18 1.49 SMR 87^ 268` *p= .06. one-tailed test Mortality Experience in a VCM Production Plant/Buffler et al r &S 001472 lortality Experience of Workers [in a Vinyl Chloride Monomer roduction Plant 3f gi; Patricia A. Buffler, Ph.D.; Susan Wood, M.A.; Clayton Eifler, Ph.D.; Lucina Suarez, M.S.; and Duane |. Kilian, M.D. 0he evidence associating exposure to vinyl chloride the risk of tumors of various sites, including lung _ancer, is inconsistent. In 1976 a mortality follow-up study $464 white males employed in a vinyl chloride monomer rCM) production plant since 1948 was conducted. Vital atus was ascertained for 100% of the cohort. Eight 85%) of the 28 deaths observed were due to malignant oplasms. No angiosarcomas or other liver tumors were i. A statistically significant excess was noted for talignant neoplasms of the respiratory system (p=.03). effect of smoking, duration of exposure to VCM, level texposure, and the combined effect of duration and level exposure were analyzed separately. A five-year latency juirement was maintained for all analyses except for the king analysis. Levels of exposure to VCM prior to 1971 estimated from monitoring data available for the arrod 1971-75 by extrapolating the relative levels for job sifications backwards in time. Smoking histories were available for 27.6% of the cohort. When it was as1 that all "unknowns" smoked, a significant excess of oiratory cancer was still observed (p = .05) When the gunrmum latency period of five years restricted analysis to :mortality experience after five years from date of initial sure to VCM for the 314 employees satisfying this crit>n, the excess of respiratory cancer was moderate but jot significant (p = .06). Both a longer duration and a higher si of exposure during the first five years following the fate of initial exposure were associated with a statistically fygn'tficant excess of respiratory cancer (p=.02 and p~.03, $pectively). However, when duration and level of sure were combined in an overall exposure index, the Ku/ts were not significant (p = .07). The discrepancy in the $so/ts from the dose-response analyses may be due to the the University ol Texas School of Public Health. PO Box 20186. TX 77025 (Dr. Buffler and Ms Wood and Suarez), Department of Medicine and Community Health. University ol Texas Medical Galveston, TX 77550 (Dr Eifler). and Occupational Health and Research, Dow Chemical Companv. Freeport. TX 77541 (Dr Kilun) J^^rna| of Occuoaiional Medic|ne/Vl 21 No 3/March 1979 potential error in the estimated levels and the small number of events observed, but the results do suggest that a relationship exists between exposure to VCM and respiratory cancer. The association of vinyl chloride and the develop ment 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.'". 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 workers in a vinyl chloride polymerization plant.* 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 the liver.* Seven of the workers cleaned reactors, and the rest were either operators or maintenance personnel. In itial exposures for all cases occurred before 1962. Following early reports, several epidemiologic studies of workers exposed to 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 to all 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 195 tionate mortality ratios, which are not specifically a measure of risk. In 1974, Tabershaw and Gaffey1 published results of an industry-wide historical prospective study of 8,384 workers involved in the manufacture of vinyl chloride and vinyl chloride polymers in 33 plants. The study was restricted to individuals who had at least one year of ex posure to vinyl chloride before December 31, 1972. Ex cesses for. the specific causes of death were not statisti cally significant, except for cancer of the digestive system, consisting primarily of previously identified angiosarcomas of the liver. The excesses for cancers of the respiratory system and lymphomas, while not statistically significant, were suggestive of possible risks which appeared to be related to the dose of vinyl chloride. Dose was measured by an average monthly ex posure score determined for each worker and based on a subjective estimate of relative levels of exposure for jobs within each plant. The authors quite correctly point out that exposure levels between plants may not have been comparable. In addition, the inclusion of many workers with inadequate latency periods, some as short as one year, may have obscured the exposure effects This study had been extended to more adequately evaluate latency and to include more complete information regarding the study cohort.' The final report is therefore based upon a total group of 10,173 employees from 37 plants, of whom 9,677 (95.1 %) were successfully traced. While there were no statistically significant excesses of site specific malignancies except for liver (angiosarcoma) and brain, the risk of malignant neoplasms of the respiratory system does appear to be associated with intensity of exposure -- a standardized mortality ratio of 92 for the low intensity category compared to that of 141 for the high intensity category. In a study presented at the New York Academy of Science conference on vinyl chloride, Nicholson et al1 described an excess in total mortality and in overall cancer mortality among 257 men with five or more years of exposure occurring before 1963 in a polymerization plant. In addition, they reported three deaths due to an giosarcoma of the liver, one due to cancer of the brain, two due to lymphoma and none due to lung cancer. Two additional mortality studies10 " resulted in essen tially negative results. One of these, a mortality follow-up study of 594 employees at the Dow Chemical Company polymer plant in Midland, Michigan, by Ott et al,' re vealed excesses in overall cancer only in the high ex posure category (> 220 ppm). In this study, evaluation of the effects of vinyl chloride was confounded by the fact that 72 of the 594 employees had also been exposed to arsenic, a known carcinogen affecting the respiratory system. Analysis of the mortality experience among the cohort without the aresnic exposed workers indicated a statistically significant increase in mortality due to malig nant neoplasms, particularly lung cancer, among workers exposed to levels of vinyl chloride above 220 ppm. Duck et al" found no significant excesses in overall or cause specific mortality in a British Petroleum chemical industry population of 2,120 male workers exposed to vinyl chloride. The analysis included a separate evalua tion of mortality for autoclave workers (reactor cleaners), polymer plant workers, and monomer plant workers. The authors observed no relationship between length of ex posure and risk of cancer. This particular analysis, however, has been challenged as methodologically inap propriate due to the misallocation of person-years." In 1975, the National Institute for Occupational Safety and Health reported results from a follow-up study of 1,294 workers at four polymerization plants, two of which also produced vinyl chloride monomer.1 All workers in cluded in the study had been exposed ror five or more years with at least ten years' latency period (ten years since initial exposure). Significant risks for cancer of the liver, lung, brain and central nervous system were found for workers with 15 years of latency. An increased risk was also observed for lymphatic and hematopoietic cancers. By contrast, the study reported by Fox and Collier11 of 7,000 workers exposed to vinyl chloride in the British in dustry did not indicate that cancers other than those of the liver were associated with exposure to vinyl chloride monomer. In this Study initial exposures for a fairly high proportion of the workers occurred after 1960, and follow-up by three of the eight factories was poor. In addi tion, the determination and analysis of exposure were questionable in that a measure of level of exposure ascer tained retrospectively and subjectively by the par ticipating industries was used rather than duration of ex posure. some combination of level and duration, or specific job classifications. Some background information on vinylidene chloride (VDC), a structurally similar chlorinated hydrocarbon, is also important in this review since exposures to VDC at lower concentrations often occur simultaneously in the VCM production area studied. VDC is a known hepatotoxin11 and has been recently described as a genetically active compound in the bacterial test systems used." '* The literature contains only one report on the health and mortality experience of workers exposed to VDC without simultaneous exposure to vinyl chloride." In this study of 138 workers, Ott et al" reported no excess mortality due to malignant neoplasms or adverse health effects at tributable to exposure to vinylidene chloride. Based upon this review of the literature, the evidence associating vinyl chloride with the risk of tumors at various sites is strongly suggestive. However, some results, particularly those reported for lung cancer, are in consistent, and several questions remain regarding the strength of the association and the effects of varying levels of exposure. The present study was undertaken to further delineate the carcinogenic risk associated with ex posure to vinyl chloride by utilizing more definitive infor mation regarding duration and level of exposure, to evaluate the effects at lower doses, and to address some of the methodological problems found in other studies." " 10 Although it would be desirable to evaluate the specific effects of vinylidene chloride in the popula tion studied, unfortunately, it is not possible to separate its effects from those of vinyl chloride. Materials and Methods J Subjects of this investigation were persons employed im a vinyl chloride monomer production plant of the Dow 196 Mortality Experience in a VCM Production Plant/Butfler et al Jtendix B. Under the extreme assumption that all ^unknowns" actually smoked, the expected number of Inspiratory cancer deaths for the 464 white males is 1.98. jyvith five deaths observed, this excess is of borderline significance (p = .05). Since it is extremely unlikely that all persons in the "unknown" category smoked, smoking appears to be an unlikely explanation for the excess spiratory cancer mortality. ^Effect of Five-Year Latency The latency period for occupationally induced cancers |fnay range from five to 20 years from the date of first exsure. In the above mortality comparisons, the ex- jperiences of all workers, regardless of the length of time lelapsed since initial exposure, are included. This techfpique may mask the effects of exposure in that a suffi cient latency period may not have accrued prior to death For observation. When the SMR's in Table 4a were [recalculated utilizing a minimum latency period of five Shears from the date of initial exposure to vinyl chloride, j|he resulting SMR for malignant neoplasms for the 314 femployees satisfying this criterion was slightly lower, 268 tyersus 289 (Table 4b). sS' (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 ent in a vinyl chloride area for all 464 workers was 4.6 Shears. The values ranged from a minimum of two months [to a maximum of 26.9 years. It is important to determine whether increased duraXp.oh of exposure is associated with higher mortality. When |lddking for such a relationship, bias may occur if the ex:posure and observation periods overlap.20 Death may ter.minate exposure prior to the satisfaction of some minimum exposure requirement, so that some deaths fall 1 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. Person-years 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 ideaths 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 Journal of Occuoafionai Medicine/Vol. 21. No, 3/March 1979 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 the 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 alive 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 Exposure Storting Date j August 1,1948 Observation Cut off Date January Sept.25, Sep). 25,1 1964 1970 1975 i -4 _L_ Individual! A individual B e------ -- Hfc-; ----- ;X Initial 5 yr. Observation period period Inilial 5 yc Observation period ! period individual C i------- !-- Initial 5 yrperiod eiposure no exposure Fig 1. -- Example of determination of duration of exposure during five years following date of initial exposure to vinyl chloride for three employees exposed prior to date allowing far 5-year latency (September 25, 1970). The initial date of exposure tor Individual A was January 1, 1964, prior to September 25, 1970 (the cutoff date minus 5 years). He died on January 1,1975, Since Individual A was continuously exposed tor the entire five-year interval from the date 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 B was exposed for only two years during the five-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 five-year interval was net completed prior to September 25, 1970 (the study cutoff date minus 5 years) and were therefore excluded from these analyses. 199 R&S 001474 Table 5. -- Observed and Expected Deaths Among 314 White Males in a VCM Production Plant by Initial Five-Year Duration of Exposure.* Initial 5-Year Duration (Years) Short (< 2.29) Long ( >2.29) No. of Persons 157 157 PersonYears 1123 2227 Obs. 7 15 All Causes Exp. SMR Obs. All Malignant Neoplasms Exp. SMR Malignant Nealasms of the Respiratory System Obs. Exp. SMR 7.75 17.43 90 1 86 5 1.32 3.02 76 0 166 4 .45 1.05 0 3811 * For 314 individuals exposed before September 25, 1970 and exposures incurred before that dale, counting deaths occurring five or more years after initial exposure t p = .023, one tailed test 6. Again, there is a statistically significant excess of respiratory cancer in the group with a high average level of exposure (3 deaths observed vs. .68 expected, p = .032). 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 SMR, 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 differ in cer tain demographic or environmental characteristics related to mortality. Lastly, the elimination of a signifi cant number of individuals from the study reduces the precision of the estimate of the SMR. 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 the 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 follow-up are similar when comparing overall mortality between the two groups, but that results differ somewhat when comparing mortality due to malignant neoplasms, specifically malignant 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 1970, 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.2" 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 noted, workers in the cohort under study were simultaneously exposed to VCM vapors and varying Table 6. -- Observed and Expected Deaths Among 314 White Males in a VCM Production Plant by Estimated Relative Level of Exposure (or Initial Five-Year Exposure Interval.* Avg. Level of Exposure During Initial 5 Years* No. Of Persons PersonYears Obs. All Causes Exp. SMR Obs. All Malignant Neoplasms Exp. SMR Malignant Neoplasms of the Respiratory System Obs. Exp. SMR Low High 160 1374 10 13.56 74 2 2.38 84 1 82 122 154 1977 12 1162 103 4 1.95 205 3 .68 441* * For 314 individuals 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 t 8ased on 1971-75 monnoring data t p = .032. one-taiied test 200 Mortality Experience in a VCM Production Plant/Buffler et al 1 Table 7. -- Observed and Expected Deaths Among 314 White Males in a VCM Production Plant by Exposure Index for Initial Five-Year Exposure Interval.* i P- Initial 5-Year & Exposure Indexf No. of Persons PersonYears Obs. All Causes Exp. SMR All Malignant Neoplasms Obs. Exp. SMR Malignant Neoplasms of the Respiratory System Obs. Exp. SMR a' Low ? High 157 1143 9 9.40 95 3 1.62 185 1 .56 180 157 2207 13 15.79 82 3 2.72 110 3 .94 319$ jgt. Tp|i. * For 314 individuals exposed before September 25, 1970, exposures incurred during the live-year interval from dale of initial exposure, and counting deaths occurring five or more years after initial exposure f Based on 1971-75 monitoring data j p= .07. one-tailed test Concentrations of vapors from the production of VDC, Jfijthylene dichloride, methyl chloroform and ethyl doride. A weakness of most mortality studies of ^chemical indistry employees is that workers may have an exposed to many other chemicals while working in Sther areas of the production facility or in other chemical ipanies before or after the period of specific observa0ion.We were able to determine that no members of the gcbhort had been exposed to arsenic or asbestos while ey 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 sof exposure were higher before 1971, the ratios of levels for any two job classifications remained approximately jfconstant. It is believed that reasonable estimates of the ^relative levels of exposure prior to 1971 were made by ackwards extrapolation of post-1971 exposure data, jk It is also important to note that initial exposure to vinyl hloride occurred in mid-career (34-43 years of age) for all Jour persons who died of lung cancer (Table 3). In this gard, the lack of information on previous employment |pr occupational exposures for these individuals adds to kthe difficulty of interpreting the significance of these ^'Statistical findings. t" 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 in 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 1.05 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 this 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 heavily dependent on this assumption. Possible ex planations for the fact that statistical significance was observed in two of these analyses, but not the levelduration index, may be due to the potential error 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 not 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," However, when the 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. f____ Limited follow-up Complete follow-up Table 8. -- Observed and Expected Deaths Among White Males in a VCM Production Plant by Type of Follow-Up. No. of Persons PersonYears Overall Malignant Malignant Neoplasms Mortality Neoplasms of the Respiratory System Obs. Exp. SMR Obs. Exp. SMR Obs. Exp. SMR 335 3067 18 20.55 88 6 3.43 175 5 1.16 431 * 464 5313 28 31.63 89 8 5.19 154 5 1.73 289f p = 007. one-tailed test t p= 032 Journal o! Gccuoauonai Medicine/Voi 21 No 3/March 1979 201 R&S 001476 "1 f, A Although the SMR is an adequate measure of excess mor tality as compared to the mortality of a standard popula tion, the comparison of two SMR's depends not only on the differences in the age specific mortality rates of each group from the standard, but also on the age specific population weightings of the two groups. Thus, it is entire ly possible, if the age distributions are vastly different, that the two study groups might have equal age specific mortality rates but somewhat different SMR's. Despite the problems in the use of SMR's, no alternative was con sidered because of the small numbers involved. Conclusions In 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 vinyl chloride. However, the fact that excesses were seen in the group with the longer duration of exposure in the initial five years, and in 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 the 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 inconsistent reports to date, more studies of the specific dose relationships and confounding exposures are needed. This study was funded bv a research award from Dow Chemical Co . U S A The authors wtsh to acknowledge the support and assistance or the various Departments of Dow Chemical Co. Texas Division and U S.A . without whom this study could not have been conducted' the Occupational Health and Medical Research Department, the Industrial Hygiene Department, the In dustrial Medicine Department and the Personnel Department The critical review of this report by Dr, Ralph Cook. Dow Chemical Co. USA and the assistance provided bv the UTM0 Pathology Department the Umversitv of Texas at Houston Education and Research Computation Center, and the En vironmental Epidemiology Branch of the National Cancer Center m reviewing and processing data is acknowledged This paper was issued as the Dow Technical Release 8-60CMfl7'78 References 1. Monson RR and Peters IM: Proportional mortality among vinyl chloride workers. Lancet 2:397-393, 1974 2. Tabershaw IR and Gaffey WR: Mortality study of workers in the manufacture of vinyl chloride and its polymers. I Occup Med 16 509-518. 1974. 3. Nicholson W|, Hammon EC, Seidman H, and Sellkoff II. Mortality experience of a cohort of vinyl chloride-polyvinyl chloride workers Ann NY Acad Sci 246:225-230. 1975. 4. Waxweiler R|, Stringer W, Wagoner )K, and lones I Neoplastic risk among workers exposed to vinyl chloride Ann NY Acad Sci 271:4048. 1976. 5. Infante P, Wagoner |K, McMichael A|. et at Genetic risks of vinyl chloride. Lancet 1:734-735.1976 6. Creech |L and lohnson MN. Angiosarcoma of liver in the manufac ture of polyvinyl chloride. I Occup Med 16150151, 1974. 7 Block ): Angiosarcoma of the liver following vinyl chloride exposure, IAMA 229:53-54, 1974. 8. Delorme F and Theriault G: Ten cases of angiosarcoma of the liver in Shawmigan, Quebec. I Occup Med 20:338-340. 1978 9 Equitable Environmental Health, Inc: Epidemiologic study of vinyl chloride workers- Final report submitted to Manufacturing Chemists Association. January, 1978 202 10 Ott MG. Langner RR, and Holder BB. Vinyl chloride exposur controlled industrial environment. Arch Environ Health 30-333-339. 11 Duck BW. Carter |T, and Coobes E): Mortality study of worke polyvinylchloride production plant. Lancet 2.1197-1199, 1975^ 12. Wagoner |K and Infante PE: Vinyl chloride and mort^^^.et: the Editor, Lancet 2.194-195, 1976. 13. Fox A| and Collier PE. Mortality experience of workers expo: vinyl chloride monomer in the manufacture of polyvinyl chloride in Britain. Br / Ind Med 341-10, 1977. 14. lenkms LJ, Trabulus Ml. and Murphy SD. Biochemical effe 1,1-dichloroethylene in rats: Comparison with carbon tetrachloride 2-dichloroethylene. Toxicol Appl Pharmacol 23.501-510, 1972. 15. McCann I, Choi , Yamasaki E, and Ames BN: Detection o cinogens as mutagens in the Salmooella/microsome test Assay o chemicals. Proc Natl Acad Sci 72.5135-5139,1975. 16. Bartsch H, Malavedle C. Montesano R. and Tomato L T mediated mutagenicity of vinylidene chloride and 2-chlofObutadiene Typhimunum Nature 2SS.641-653, 1975- 17. Ott MG, Fishbeck WA. Townsend MS, and Schneider El: A h study' of employees exposed to vinylidene chloride. I Occup 18.735-738, 1976. 18. Pasternak BS and Shore RE: Statistical methods of assessing following exposure to environmental carcinogens, in Environm Health: Quantitative Methods. A. Whittemore (Ed.) Philadelphia: So for Industrial and Applied Mathematics. 1977, pp 49-71. 19. Liddell FDK, McDonald |C, and Thomas DC: Methods of cc analysis Appraisal by application to asbestos mining. 1 Royal Stat 140469491. 1977 20. Enterlme PE: Pitfalls in epidemiological research. I Occup 18 1 50-156. 1976. 21. Buffler PA, Wood 5M, Suarez L, and Kilian D|: Mortality folio: of workers exposed to 1,4-dioxane. I Occup Med 20:255-259,1978. 22. Kahn HA: The Dom Study of smoking and mortality among veterans: Report on eight and one-half years of observation. Nati< Cancer Institute Monograph No 19, 1-125, U.S- Department of He. Education, and Welfare, lanuary 1966. 23. U S. Department of HEW: Changes in cigarette smoking habits tween 1955 and 1966. Public Health Service Publication No. 1000, Sr 10, No. 59, U.S Government Printing Office, Washington, 24. ACGIH: Threshold limit values for 1960. AMA Arch 1:62. 1960 25. Torkelson TR, Oyen F, and Rowe VK: The toxicity of vinyl chioi as determined by repeated exposure of laboratory animals. Am Ind I Assoc I 22:354-361. 1961 26. Department of Labor, Occupational Safety and Health Admims tion: Exposure of vinyl chloride Federal Register 39J5890-3S898, Parr October 4, 1974 27. Ederer F and Mantal N Confidence limits on the ratio of t Poisson variables. Am I Epidemiol 100:165-167,1974 Appendix A Estimated Time Weighted Average (&-Hour) Exposure to Vinyl Chloride by Job Classification, 1971-1975 Percent of Total Average Person-Yea Job Classification 8-Hr. TWA Exposed 1. Control lab personnel 22.3 4.7 2. Development lab personnel 4.1 5.7 3. Production personnel Control A 7.7 16.6 Control B 2.8 7.5 Control C 44 8.9 Class 3 operators -- .8 Total 57 33.8 4. Loaders and plant men Class 1, 2 operators Head packaging operator 7.1 12.3 Material handling operator 21 Mortality Experience in a VCM Production Plant/Buffler et i R&S 001478 Packaging operator, service technician Total tertain supervisory If positions S' Production superf intendent, assistant production superinten dent, production engi neer, R&D engineer, engineer, safety engi neer, Sr. production engineer. Parts technician, Sr. Manager Assistant engineering technician Ceneral superintendent, section superinten dent, superintendent, supervisor, assistant superintendent, plan ning engineer, material control clerk, plant assistant, head clerk, chief material handling technician, shipping coord inator.maintenance coordinator, maintenance engineer Total f Maintenance personnel Boilermaker, apprentice Welder, apprentice Machinist, apprentice. helper, crew leader Pipefitter, apprentice. helper Utility man Instrument technician Production foreman, shift foreman Maintenance foreman Utility crew leader, rotating shift foreman, foreman Total .1.9 .2 .3 .0 1.8 1.4 .2 1.1 1.7 .2 3.2 4.3 .4 2.5 .1 16.4 9.3 .1 .2 .0 1.9 11.6 1.2 1.1 1.7 4.2 1.2 37 5.5 .2 5.2 24.0 7. Other personnel Electrician, apprentice Loading supervisor. technical foreman, coverer, |anitor, elec trical foreman Total All groups combined 3.8 -- 3.8 5.4 2.0 1.8 3.8 100.0 For some lob classifications there were no monitoring data available lor the inter val 1971-75 The value assigned was determined by averaging all monitonng data available for 10b classifications within the group to which the specific iob classifica tion was assigned The averages computed were weighted accoidng to total personyears in the cohort spent in each iob classification 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. white male veterans for the years 1954 to 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" reflect the correspon ding percentages for the Texas white male population in the time periods 1950-59 and 1960-69. respectively. Using these two assumptions, a set of age specific rates for the Texas white male population according to smok ing status was constructed for use as a standard, in the following manner. Let M.= cause specific mortality rate for age group i Mn-- cause specific mortality rate for smokers in age group i M= cause specific mortality rate for nonsmokers in age group i Si= proportion of population in age group i who smoke r.= age specific relative risk for smokers com pared to nonsmokers Then Mi = sM* + (T-Si) Mn = M (si r. + (1 -sj] M<i = Mi / [s,r, + (1-5i)]; M = rain. 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. -- from "When Values are SubsOtuted (of Truth" by J, Bennett, in The Waff Sueef lournil |u!v 25. 1978 Journal of Occupational Medicme/Vol 21. No. 3/March 1979 203