Document ZBpV0p6On3ZmZm2xwZVYw2w1J

757 759 760 761 762 763 764 765 -A Running title: Brain Gliomas in a Texas Chemical Plant ECE IVED AUG 2 4 1984 . ------- ----..... - - SCHNATTER Neuroepidemiology 6 Case-Control Study of Gliomas of the Brain among Workers Employed by a Texas City, Texas Chemical Plant Sanford S. Leffingwell, Richard Waxweiler, Victor Alexander^toward R. Ludwig, William Halperin National Institute for Occupational Safety and ^eaJth, Cii^tnati, Ohio, USA 759 Key Words. Petrochemicals . Brain tumors Occupation Residence 771 H 772 H 773 774 775 776 777 H 778 779 Abstract A Texas petrochemical plant had elevated standardized mortality ratios for neoplasms of the brain. A case-control study examined possible associations between gliomas of the braih and job title, departmental employment history, chemical exposure history.`geographic location within plant dates of employment, and residence. The greatest apparent nsks were associated with exposure to carbon dioxide, diethyl suifete, diethylene glycol, ethanol, ethylene, isopropanol, methane, tetraethylene glycol, and vinyl acetate; with first employment in the 1940s or early 1950s, and with residence in La Marque, Tex. No significant differences between cases and controls wen apparent in duration of exposure to any of these chemicals. 792 Introduction 7g4 In February 1979, the National Institute for Occupational Safety and 785 Health (NIOSH) and OSHA, with the aid of the company management, 786 began an investigation of a cluster of primary brain tumors at a chemicals 787 and plastics plant in Texas Qty, Tex. Alexander et al. (11 have described the H 88 characteristics of the brain tumor cases and the methods for case identifiH 89 cation. Two retrospective cohort mortality studies ofall male hourly work790 ers employed at this plant from 1941 through 1977 have been reported [2, 791 3]. Findings included an overall standardized mortality ratio [SMR 100 792 (observed/expected)] for benign, malignant, and unspecified neoplasms of 793 the brain of 206 (p < 0.05). For those who worked more than 20 yean at 794 the plant (i.e., who began work before 1957), the SMR was 377 (p < 0.05^ 795 [2]. No other cancen were found significantly in excels ofexpected, and the 796 overall SMR was not elevated. We here describe a nested case-control study 797 of primary brain tumor cases among the employees of that plant. 798 Austin and Schnatter [4] have recently published a parallel study which 799 showed no association between exposures in the plant and brain gliomas. 800 They used deceased employees whose deaths were known to the company 801 as controls for the same cases, employed an unmatched design, and did not 802 include .analysis of residence. They were able, however, to use multiple 803 comparison groups; one group excluded controls who had died of other 804 malignancies while another permitted such decedents as controls. Subsets H 05 of these groups including only hourly employees permitted further refine806 ment. These two studies are thus different enough to be complementary, 807 not duplicative. I) I UCC 097483 / g jo Methods and Materials gj2 Case Identification * g 13 A total of23 possible cases were identified: the company documented 12 cases from H 814 death certificates in their possession; lists of all adult males who were residents of sur8 15 rounding counties and who died of malignant brain tumors between 19S0 and 1977 were gl6 matched with company employment records, yielding 4 additional cases; another 3 cases g 17 became ill and died during the course of the study; and 4 additional deceased cases were gig, found in the course of completing the cohort mortality study. We were able to obtain g 19 medical records for 20 of the possible cases and tissue specimens for 10. 820 The Armed Forces Institute of Pathology (AFIP) reviewed the tissue specimens. 821 Where different diagnoses were recorded for the same patient, AFIP reviews were ranked g22 first, autopsy reports second, surgical pathology reports third, diagnosis from the hospital 823 chart fourth, and death certificate diagnosis last; the highest-ranked diagnosis was used for 824 825 fi*** tfudySince gliomas are carcinomas, arising from ectodermal tissue of the neural crest, H g26 while meningiomas arise from mesodermal embryonic tissue, we followed the recommen- 827 dations of Schoenberg et al. [3], and limited consideration in this study to the 17 gliomas 828 among the 23 former employees with death certificate diagnoses of brain tumor. This 829 eliminated I case with a metastatic brain tumor from an unknown site, 1 who had been 830 thought clinically to have a brain tumor but was found at autopsy to have a congenital 831 faalformation and no tumor, and 4 meningiomas. A summary of the cases excluded and 832 included is given in table I. gj4 833 835 837 838 839 840 84] 842 843 844 Selection afControl Subjects For each case, a pool ofmatched potential controls was drawn from the cohort ofall people ever employed at the plant Matching criteria were: race and sex matched the case; year of birth was within 3 years of the case's; date of first employment at the Texas City plant for the control was before that of the case, but year of first employment at the Texas City plant was not earlier than 3 years before the case's; the date the control was last employed was later than the case's last date ofemployment; the control, ifdead, must not have died ofa malignancy. For each case. 6 controls were then drawn by random number from the pool of employees meeting these criteria. No control was used for more than 1 case. Some cases and controls had prior experience in refineries or chemical plants, but the information available was, in our judgment, insufficient for analysis. g4g H 847 848 849 830 831 832 853 854 855 856 857 858 H 839 86o H 861 862 863 864 Data Collection * 1 For each case and control, plant personnel completed coding sheets containing demo- graphic data, date of each new job title or department code, job code, department code. date ofeach layoff, date offinal termination (ifno longer employed at the plant), and vital status (when known). NIOSH/OSHA researchers independently verified the accuracy of the coding. Plant personnel provided translations for the job and department codes, indicated which department codes formed larger major department groups, and provided a list of chemicals used, produced, or redistributed in each department group. A `department group' is an operational unit of the plant manufacturing related products and within which employees often remained over fairly long periods. The departmental coding schemes used for accounting purposes within the plant have changed over the years, so a common list tracing the history of each department was prepared. Plant engineers were able to characterize the chemical feedstocks, outputs, and inter- mediate products of each department through the years the plant has been in operation. Since industrial hygiene data were available only for recent years and for certain corn- pounds, we equated the presence of a chemical in a depanmem with potential worker exposure. This assumption was clearly not always accurate, nor were exposures necessanlv equal in'two departments using the same chemical. i. I UCC 097484 / 866 Analysis 867 For eachjob, department, major department group, or chemical exposure common to 868 at least 4 cases, an odds ratio was calculated and tested for possible statistical significance 869 by Manteland Hatasset's [6] procedure, using the matched data programs ofRothman and 870 Boice [7]. Analyses were conducted for periods less than 13 years before the death of the 871 case, 13 or more years before the death of the case, and any time before the death of the 872 case (a case exposed for greater than 13 years and dying soon after last exposure would be H 873 counted in all three periods). Since this approach is a multipie-significance testing tech H 874 nique which should lead by chance to the finding ofapproximately one 'statistically signif H 873 icant' positive association, using a 90% (two-sided) confidence interval, for every 20 inde 876 pendent jobs, departments, or exposures considered, it is used here as an exploratory or 877 hypothesis-generating mechanism; the probability values and confidence intervals cited 878 throughout the paper are given only to show relative strength of associations. 879 Only those portions ofthe controls' work experiences which occurred during the time 880 the corresponding case was employed were considered in this analysis, since the matching 881 criteria selected controls with longer total work histories than the cases'. H 882 Duration ofexposure was examined for chemical exposures for which (a) the associa 883 tion with brain tumors reached statistical significance in the analyses described above or H 884 (b) previous reports suggested a possible relationship. For each chemical, cases' and con 883 trols' median months ofpotential exposure 13 years or more before death ofthe case were 886 tabulated and a rank-sum test was performed [8]. Employees with no exposure were 887 excluded. 888 Workers in a department nominally unexposed to a particular chemical could be 889 exposed to toxic airborne vapors or dusts from an adjacent department. To assess this 890 possibility, the years worked by each subject in each department group were tabulated, 891 shewing which department groups had about the expected 1:6 ratio of case to control- 892 years, which groups had disproportionately more case-years, and which had fewer. This 893 information was plotted on a map of the plant, which was inspected for dusters. 89; 895 897 898 899 900 901 902 903 904 905 906 Non-Work Factors We considered the possibility that the excess risk at the plant might be a reflection of an excess in the communities around the plant rather than a problem intrinsic to the plant A case-location service was retained to determine past places ofresidencc for the cases and controls and additional information was obtained through review of medical records retained at the plant. Analyses yere conducted for communities in whi^t at least 3 cases had lived, using a division of`ever lived* versus `never lived* in the community for periods 13 or more years before the death ofthe case, less than 13 years before the death ofthe case, and any time before the death ofthe case. The analysis ofresidence used all addresses up to the date ofthe case's death. A two-sided 90% confidence interval was calculated to display the strength ofassociation. Addresses were also plotted on a map. which was inspected for further clues to the epidemiology of this occurrence. 909 Results * py; 912 913 H 14 H 15 916 Demographics Date of first employment ofthe control subjects at the Texas City plant averaged 18.0 months before that of the cases, and the control subjects were bom, on average, 4 months before the respective case, with standard deviations 14.2 and 24 months, respectively. Only 5 controls meeting the matching criteria were available for one of the cases. / I UCC 097485 I 918 In-Plant Work History 919 `Operator' was the only job code represented by 4 or more cases: the 19 20 Mantel-Haenszel odds ratio for operators was 0.54, with = 1.84 (not 19 21 statistically!. There was no apparent commonality between the departments 922 >n which these operators had worked. H 23 When analyzed by department codes, only the maintenance depan* 19 24 ment 4 or more cases; the Mantel-Haenszel odds ratio was 0.32 with N 25 i& H = 1-37 (not statistically]. Grouping the department codes into major 926 departments yielded no new groups of 4 or more cases. H 27 When cases and controls were analyzed by potential chemical expo* 928 stires, a new problem became evident: maintenance men moved throughout 929 the plant and were exposed to many different agents in an irregular manner. H 30 Accordingly, we have examined the data in two ways: in the first, mainte- 931 nance men were considered to have been exposed to every agent in the 932 plant; in the second, they were excluded from analysis. The first method 933 may be closer to reality, indeed, maintenance men may have received 934 higher exposures to toxic chemicals than operators since, in maintenance 933 work, they must open pipes, reaction vessels, and pumps. On the other 936 hand, the assumption of exposure for all maintenance men, whether cases 937 6r controls, may tend to obscure an elevated odds ratio that might be 938 present ifexact data were available. Ofthe 505 chemicals reviewed, table II H 39 lists all chemicals to which at least 4 cases were exposed (excluding main- 940 tenance jobs). 941 Statistics for distribution of `exposures' among cases and controls are 942 presented in table III. The tables include the chemicals to which 4 or more 943 cases were exposed and which showed the strongest positive association 944 with brain tumors, plus vinyl chloride. Vinyl chloride monomer was 943 included since it has previously been associated with brain tumor excess 946 [9-11]947 Results of analyses by duration of exposure are summarized in 948 table IV. No statistically significantdifTercnces between cases and controls 949 were apparent in duration of exposure to any chemical , H 50 1 *ta mapping analysis of work locations within the plant, no signifi- 931 cant clustering of areas with proportionately more case-years than control- 952 years was detected. Analysis of work locations of cases and controls within 953 the plant offered no useful clues to the etiology of the tumors. 955 956 957 958 959 960 961 962 H 63 964 965 Residential Data Addresses could be`determined for 16 cases. The remaining case was known to have lived for 15 years in Texas City and Ih the nearby town of La Marque, but neither exact dates of residence in each community nor street addresses could be determined. Complete listings ofat least the community f residence were available for 93 of the 101 controls; partial listings, often inexplicit as to the exact date of moving from one community to another, were available for another 7 controls. No information at all was available for the residence ofjbontrol. In most instances, streets or streets and numbers could be determined, but there were many instances where informants could no longer remember street addresses of 40 years ago. I. | X M-J) J l S'fjn. c JL ) & ii UCC 097486 966 Table V shows the distribution'Of addresses among cases and controls N 67 (note: some subjects appear in both the Mess than 15 years' and `greater than 968 H 69 el 70 971 H 72 973 H 74 975 976 977 * 5 years' columns). The odds ratio for Texas City differed markedly from 1, while that for Galveston is essentially equal to 1. La Marque had an appar ent excess of cases over controls (maximum odds ratio = 5.86). It is a residential community, without heavy industry, and lies southwest of Texas City, west of the. plant, and north of Galveston. A chemical dump, established in 1959 and listed by the Environmental Protection Agency as a high-priority site for emergency cleanup, is located at the southeast extrem>ty of La Marque. Vinyl chloride levels as high as 161 parts per billion have been measured at the fence line of the dump [12], Figure 1 shows that the known addresses for the cases who lived in La Marque appear to cluster 97g 979 980 981 982 toward the southern and western parts of the city, not adjacent to either the plant or dump nor downwind from them. Drinking water for La Marque Texas City comes from deep wells, tapping the same stratum, while water for Galveston comes from the Brazos River. The average length of residence in La Marque (excluding those who never lived there) was 12.4 H 83 y*" fr cases, and 16.3 years for controls; this difference was not statist!984 cally significant. 985 986 987 988 989 990 991 992 H 93 994 995 996 N 97 Highland Bayou, a slow-moving stream draining into Galveston Bay, runs along the southwestern and southern edge of La Marque, upwind from the community. In view of the large number of publications associating glioblastomas with viral agents [13-20], a mosquito-bome virus seemed an interesting etiotogical hypothesis, as did kerosene and various insecticides used to control mosquitos during and after World War II. To separate the effects of exposures to chemicals and residence in La Marque, we classified subjects into 4 strata for each chemical according to history of exposure to that chemical (cxp+ or exp-) and history of LaMarque residence (LaM+ or LaM-). Each of 3 strata (exp+LaM+, exp-LaM+, and exp+LaM-) was compared to cases and controls who had neither risk factor (exp-LaM-); \.ej three 2X2 tables were analyzed for each chemical and the odds ratios were compared, as suggested by Kleinbaum et al. [21]. 998 We were unable to maintain the matching in this step, since too many 999 empty cells for use with the Mantel-Haenszel procedure would have N 00 resulted. Results are shown in table VI. The odds ratios generally are greater 001 for La Marque residence Without chemical exposure than f<Jr exposure to 002 003 004 H 05 individual chemicals without La Marque residence and often are quite a bit greater for exposure to both risk factors than for either one alone. During the period longer than 15 years before the death of the case for analyses in which maintenance men were excluded, only ethanol and di- and tetnjethy- 006 tene glycol show * stronger association with disease than does La Marque 007 residence. 008 In reviewing the death certificates obtained for case-finding, we found 009 that 7 (9.9%) of 71 adult male residents of Galveston County whose death 010 certificates were coded as `malignant brain tumor' and who died between OH 1949 and 1977 had La Marque addresses on the death certificate. Estimates 012 of La Marque's'population over the same period were obtained [22]. 013 Weighting the populations of the community and county for the calendar 014 years under consideration yielded crude death rates of 2.00 adult male 015 deaths per 100.000 total person-years at risk in La Marque and 1.63 for the H 16 remainder of Galveston County. The difference was not statistically signif017 icant (p = 0.33). I J J I UcC 097487 020 Discussion .^ 022 The greatest apparent risks were associated with exposure to carbon 023 dioxide, diethyl sulfate, diethylene glycol, ethanol, ethylene, isopropanol, 024 methane, tetraethylene glycol, and vinyl acetate; with first employment in H 25 the 1940s or early 1950s; and with residence in La Marque [2]. The chem- H 26 '*1 associations found may need further study, but are not convincing evi- 027 dence, particularly in view of Austin and Schnatter's [4] negative findings. 028 The association with residence is somewhat stronger. 029 Among the in-plant exposures considered, the relationship between N 30 gliomas ofthe brain and carbon dioxide is statistically significant only when 031 all work histories are included regardless of latency. We would expect a 032 carcinogen to show stronger relationships when latency was considered; the H 33 absence of a latency effect, coupled with the fact that carbon dioxide expo- 034 stues likely to be experienced by workers would have virtually no effect on 033 normal physiologic levels, eliminates C02 from further consideration. Its 036 appearance on the list serves to illustrate the pitfalls ofmultiple significance H 37 testing mentioned above and to inject a note of caution in forming conclu- 038 sions based on other associations in this report. Methane, with 6 cases 039 potentially exposed (excluding maintenance men), is similariy unlikely to H 40 be present in amounts capable of increasing exposure markedly over back- 041 ground levels produced by intestinal flora. 042 Wewere unable to find reports ofcarcinogenesis or mutagenesis testing 043 on tetraethylene glycol. Diethylene glycol was found to cause bladder stones 044 and tumors in one test using rats [23], but has not been carcinogenic or 043 mutagenic in other experiments [24, 25]. Excluding maintenance men, a 046 total of4 cases definitely worked in deportments where di- or tetraethylene 047 glycol was present. Even if the association were causative, the fraction of 048 cases attributable would be insufficient to explain the observed excess; this 049 positive finding may be the result of multiple significance testing. 030 Diethyl sulfate is considered a carcinogen and has caused brain turnon 031 in experimental animals [26]. With regard to other chemicals, a statistically 032 significant excess of brain tumors was observed in a British isopropanol 053 plant, although the numbers were very small [27]. Several other cancers 034 have been associated with isopropanol exposure, although pure isopropanol 033 is not usually consideredLcarcinogenic [28-30], Ethylene, ltyce vinyl acetate 036 and vinyl chloride, has an unsaturated two-carbon moiety. Although both H 37 ethylene and vinyl chloride are metabolized through a highly reactive epox- 038 ide stage which may alkylate organic compounds [31, 32], ethylene is not 039 mutagenic in Ames tests [Njosh, unpubl. data] and was not found to have H 60 any effect in a 2-year exposure study using rats [33]. There is less informa- 061 tion available on vinyl acetate; it is not mutagenic in bacterial assay [34, H 62 35]. Information on association with length of exposure, latency, and num- 063 ber of cases who could be attributed to the cheitiical if it were a brain H 64 carcinogen does not. point clearly toward any of these chemicals but obser- H 65 nation of other clusters or cohorts might indicate t#t one of them is danger- 066 ous. H 67 While some of the associations found could be considered weak evi- 068 dence of carcinogenicity, none was conclusive. There are wide confidence 069 intervals around all of the odds ratios given: therefore, differences between 070 odds ratios should be interpreted cautiously. 071 It is possible that a critical exposure was more general than implied by 072 the depanmcnt group analysis used here, and that use of in-plant controls 073 constituted over-matching which might have obscured a significant finding. IM 74 We know of no satisfactory way to test this possibility within the confines of 075 the present study. - / I - / ha i UCC 097488 H 76 Risk associated with La Marque residence seems greater than that asso- -H 77 ciated with the chemicals studied. La Marque and Texas City share a com- 078 mon water source, but La Marquesas a higher ratio of cases to controls 079 than Texas City, therefore a water-borne environmental carcinogen [36] 080 seems unlikely. Since there are no major chemical or other industries 081 upwind from the community, airborne industrial carcinogens do not seem H 82 to be a likely explanation for the association observed. (The wind is domi- 083 nantly out of the south-southeast.) The cases' shorter average duration of 084 residence in La Marque argues against a causal association with residence. 085 From the comparison of crude death rates for La Marque ind Galveston 086 County, La Marque does not appear to be over-represented among brain 087 tumor deaths, but this comparison does not assure that a cohort who lived 088 there in the past, some of whom have moved away, is not a greater risk. A 089 refinery adjoining this plant also appears to have an excess of brain tumors 090 aud is under study by NIOSH. Examination ofthe residence histories ofthe 091 cases who worked at that refinery showed that only 3 of 8 had lived in La 092 Marque. 093 The type of mosquito which constitutes the greatest problem in the La 094 Marque area has a range of 23-50 miles, so control measures, which relied 095 on DDT and y-benzene hexachloride until the mid 1960s, have always been 096 countywide and would not appear to explain localization to this area [37], 097 Italian farmers are reported to have higher brain tumor rates than urban 098 worker^ a finding which is statistically significant [38]. The clustering of 099 cases near the periphery of the community may be meaningful; but further 100 information is needed to understand it. 101 ' Greenwald et al. [39] have suggested that superior medical care may 102 lead to more frequent diagnoses of brain tumors among employed workers 103 with good medical insurance programs. They presented evidence of more 104 st^jpiicated diagnostic methods in Eastman Kodak employees with brain 105 tumors. Although it is reasonable to suppose such sophistication would lead 106 t0 fewer missed diagnoses of brain tumors, their report has not achieved 107 universal acceptance [40, 41] and does not directly assess the question of 108 missed diagnoses in the comparison populations. Schoenberg et al. [42] 109 found that differences between incidence rates in Rochester, Minn., where HO the Mayo Ginic provides virtually all medical care, and in Connecticut 111 were mainly due to better diagnosis at autopsy; most of the excess cases in 112 Rochester were due to meningiomas; and the differences in rates were most 113 pronounced in the older age groups. About 70% ofRochester decedents had 114 autopsies, compared to an estimated 38% in Connecticut; in Rochester, 115 60% of meningiomas were found at autopsy, compared to only 17% of 116 glioblastomas. None of the cases in this series were first diagnosed at H 17 autopsy and gliomas predominated in this group (83 vs. 40.3% in Roches- H 18 ter)- Our impression, from the medical records examined, is that the diag- H 19 noses in this case series did not hinge on either multiple or highly sophisti- H 20 cated tests, but we cannot determine the extent to which diagnostic sensi- 121 tivity bias might be a factor in this cluster. 124 Acknowledgments 125 We wish to thank the Union Carbide Corporation for freely opening their records to H 126 us and in particular Mr. Damon Engle. Plant Manager. Dr. David Glenn. GulfCoast Med- 127 ical Director, Mrs. Dorothy Heyen. Director of Personnel Relations: Mr. Robert Frantz. 128 Engineer, and Mrs. Perthan Yatankaya, Industrial Hygienist. We are also indebted to the 129 Texas Bureau of Viud Statistics and to M.D. Anderson Hospital and Tumor Institute for I jo their help in case-finding and vital status ascertainment. Messrs. Richard Miller. Ben Bare. 131 and Dans Lavnc of the OSH A hjouston South Area Office, and Dr. J tl'ilham Lloyd of the 132 OSHA Headquarters Staff provided invaluable advice throughout the study. 135 References 136 1 Alexander. V.; Leffingwell, S.S.; Lloyd. J.W.; Waxweiler. R.J.; Miller, R.L.: Brain 137 cancers in petrochemical workers - A case series report. Am. J. ind. Med. /: 115-123 138 (1980). 139 2 Waxweiler, RJ.; Alexander, V.; LefTmgwell, S.S.; Haring, M.; Lloyd. J.W.: Mortality 140 from brain tumor and other causes in a cohort of petrochemical,workers. J. natn. 141 Cancer Inst. 70:75-81 (1983). 142 3 Austin, S.G.; Schnatter, A.R.: A cohort mortality study of petrochemical workers. J. 143 occup. Med. 25: 304-312 (1983). 144 4 Austin, S.G.; Schnatter, A.R.: A case/control study of chemical exposures and brain 145 tumors in petrochemical workers. J. occup. Med. 25:313-320 (1983). 146 5 Schoenberg, B.S.; Christine, B.W.; Whisnant. J.P.: The descriptive epidemiology of 147 primary intracranial neoplasms: the Connecticut experience. Am. J. Epidem. 104: 148 499-510 (1976). 149 6 Mantel, N.; Haenszel, W.: Statistical aspects ofthe analysis ofdata from retrospective 150 studies of disease. J. natn. Cancer Inst. 22:719-748 (19S9). 151 7 Rothman, KJ.; Boice, J.D.: Epidemiologic analysis with a programmable calculator 152 (USDHEW:NIH, Washington 1979). 153 8 Hollander, M.; Wolfe, D.A.: Nonparametric statistical methods, pp. 68-75 (Wiley, 154 New York 1973). 155 9 Maltoni, C.: Predictive value of carcinogenesis bioassays. Ann. N.Y. Acad. Sci. 271: 156 431-437 (1976). 157 10 Byren, D.; Engholm, G.; Englund, A.; Westerholm, P.: Morality and cancer morbid H 158 159 ity in a group ofSwedish VCM and PVC production workers. Environ. Health Persperf/7: 167-170(1976). 160 n Waxweiler, RJ.; Stringer. W,; Wagoner, J.K.; Jones, J.; Falk, H.; Carter, C.: Neoplas 161 tic risk among workers exposed to vinyl chloride. Ann. N.Y. Acad. Sci. 271:40-48 162 (1976). 163 12 Texas Air Control Board: Vinyl chloride monomer air sampling at Texas City `Wye' 164 waste pits. La Marque, Tex., August 5-6, 1980 (Austin 1980). 165 13 Becker, L.E.; Narayan, O.; Johnson, R.T.: Studies of human papovavirus tumor 166 antigen in experimental and human cerebral neoplasms. J. can. Sci. neuroL J: 105167 109 (1976). 168 14 Birkmeyer, G.D.; Miller, F.; Mtrguth. F,: Oncoma-viral information in human glio 169 blastomas. J. ncurae Transm. 35:241-254 (1974). 170 15 Bendheim, P.E.; Dinowitz, M.: Particles resembling oncornaviruses: spontaneous 171 release from cultured meningioma cells. Archs NeuroL 34:105-108 (1977). 172 16 Cuatico. W.; Cho. J.-R.; Spiegelman. S.: Molecular evidence for a viral etiology of 173 human CNS tumors. Acta neurochir. J5:149-160 (1976). 174 17 London, W.T.; HoufT, S.; gladden. D.L.; Fucrillo. DA.: GraveU, M-: Wallen, W.C.; N 175 Palmer, A.E.; Sever, J,l_: Brain tumors in owl monkeys inoculated with a human 176 polyoma virus (JC virus). Science 201: 1246-1249 (1978). 177 18 Ida, N.: Ikama. Y.; Ogawa. JC; Takada. M.; Sugano, H.: Cell culture from a rat brain H 178 179 tumor induced by intracerebral inoculation with murine sarcoma virus. J. natrf Can cer Inst. S3:431-447 (1974). * 180 19 Tanaka. R.; Koprowski, H.; Iwasaki. Y.: Malignant transformation of hamster brain 181 cells in vitro by human papov*virus BK.. J. natn. Cancer Inst. 56:671-673 (1976). 182 20 Yung, W.K.; Blank. N.IC; Vick, N.A.: `Glioblastoma' - Induction of a reproducible N 183 184 autochtonous tumor in rats with murine sarcoma viws. Neurology 26: 76-83 (1976). 185 21 Klcinbeum. D.G.: Kupper, L.L; Morgcnstern. H.: Epidemiologic research: Principles 186 and quantitative methods, p. 407 (Lifetime Learning Publications. Belmont 1982). 187 22 City of La Marque. Tex.. Comprehensive Planning Program: Economic develop 188 ment. capital improvements, environmental assessment (Wise. Dallas 1981). 189 23 Fttzhugh. O.G.: Nelson, A.A.: Comparison of the chronic toxicity of triethylene gly 190 col with that of tetraethylene glycol. J. ind. Hyg. Toxicol. 28:40-43 (1946). 191 24 Weil. C.S.; Carpenter. C.P.: Smyth, H.F.: Urinary bladder calculus and tumor 192 response following either repeated feeding of diethylcne glycol or calcium stone 193 implantation. Ind. Med. Sutg. 36: 55-57 (1967). i. I / t UCC 097490 -\ 194 25 Pfeiffer. E.H.: Dunkclberg. H.: Mutagenicity of ethylene oxide and propylene oxide 195 and of the glycols and halohydrins formed from them during the fumigation of foods. 196 Food Cosmet. Toxicol. 18: 115-118 (1980). 197 26 Druckrey, H.; Kruse, H.; Preussman. R.; Ivankovic, S.; Landschutz. G: Cancerogene 198 alkylierende Substanzen. III. Alkylhalogenidc, Sulfate, Sulfonate, und ringgespannte 199 Heterocyden. Z. Krebsforsch. 74:241 (1970). v 200 27 Alderson, M.R.; Rattan, N.S.: Mortality ofworkers on an isopropyl alcohol plant and 201 two MEK dewaxing plants. Br. J. ind. Med. 37:85-89 (1980). 202 28 Enterline, P.E.; Lilis, R.; Alexander, V.; Mahoni, G: Importance ofsequential expo 203 sure in the production ofepichlorohydrin and isopropanol. Ann. N.Y. Acad. Sci. 381: 204 344-349(1982). 205 29 Weil, CS.; Smyth, H.F.; Nale. T.W.: Quest for a suspected industrial carcinogen. 206 Aichs ind. Hyg. occup. Hlth 5:535-547 (1952). 207 30 Htieper, W.C.: Occupational and environmental cancers of the respiratory system. 208 Specific occupational cancers and their environmental counterparts (Springer, New 209 York 1966). 210 31 Ehrenberg, L; Osterman-Golkar, S.; Segerback, D.: Svennson, K.; Calleman, CJ.: 211 Alkylation of haemoglobin alter metabolic conversion of ethene to ethene oxide in 212 vivo. MutaL Res. 43:175-184 (1977). 213 32 Green, T.; Hathaway, D.E.: The biological fate of vinyl chloride in relation to its 214 oncogenicity. Chem.-biol. Interactions 11:545-562 (1975). 215 33 Gralla, EJ.: A twenty-four month inhalation toxicology study in Fischer-344 rats H 216 exposed to atmospheric ethylene (Chemical Industry Institute of Toxicology, Re 217 search Triangle Park 1980). 218 34 Bartsch, H.; Montesano. R.: Prescreening ofenvironmental and industrial chemicals 219 in a series of short-term tests for the detection of potential carcinogens. Comm. Eur. 220 Communities (Rep.) EUR; ISS EUR 6388, Environ. Res. Programme, pp. 269-373 221 (1980). 222 35 Ujinsky, W.; Andrews, A.W.: Mutagenicity ofvinyl compounds in Salmonella typhi- 223 murium. Teratog. Carcinog. Mutagen. 1:259-267 (1980). 224 36 Cantor. K.P.; Hoover, R.; Mason, J.T.; McCabe. t_J.; Associations of Cancer mor 225 tality with halomethanes in drinking water. J. natn. Cancer Inst 61: 979-985 226 (1978). 227 37 Mix, D.: Personal communication. 228 38 Musicco, M.; Filippini, G.; Bordo. B.M.: Melotto. A.; Morello, G.; Berrino. F.: Glio 229 mas and occupational exposure to carcinogens: case-control study. Am. J. Epidem. 230 116:782-789 (1982). 231 39 Greenwald, P.; Friedlander. B.R.; Lawrence. C.E.; Hearne. T.; Earle, K.: Diagnostic 232 sensitivity bias - an epidemiologic explanation for an apparent brain tumor excess. J. 233 occup. Med. 23:690494 (1981). t 234 40 Gann, P.; Rosenman, K.D.: Conclusions questioned in brain tumor excess study. J. 235 occup. Med. 24:428 (1982). 236 41 Greenwald. P.; Friedlander. B.R.; Lawrence. C.E; Hearne, T.; Earle, K.: Author's 237 response. J. occup. Med. 24:428-432 (1982). 238 42 Schoenberg, B.S.: Christine. B.W.; Whisnant, J.P.; The resolution of discrepancies in 239 the reported incidence of primary brain tumors. Neurology 28:817-823 (1978). 243 Sanford S. Leffmgwcll. MD. MPH. 244 National Institute for Occupational Safety and Health. 245 4676 Columbia Parkway.j^ 246 Ccincinnati: OH 45226 (USA)J" CT # t. UCC 097491 / N 000 AN 1 :NNEPI044XA.96 LOOt Table L Cases from cohort study included in and excluded from case-control study 002 Diagnosis Included Excluded 005 007 008 010 on 013 014 016 018 020 022 024 026 029 Gliomas Glioblastoma multiforme (includes diagnoses ofastrocytoma grades 111 and IV) Thalamic glioblastoma suspected clinically; no tumor in biopsy of abnormal appearing area of brain cortex Pituitary adenocarcinoma suspected clinically; radiotherapy followed by proven glioblastoma 12 years later Astrocytoma grade II Metastatic tumor, unknown primary Brain tumor suspected clinically, not found at autopsy Mcningidma, malignant .Meningioma, benign Subtotal Total 17 14 1 l 1 17 23 1 1 3 1 6 L 034 Table IL Chemicals to which four or more cases were exposed 035 036 037 038 039 040 041 042 043 044 045 068 Acetaldehyde Acetic acid Acetone Carbon dioxide Diethanolamine Diethyl sulfate Diethylene glycol Ethanol Ethylene Ethylene dichloride Ethylene glycol Hydrochloric add Hydroxypropyl acrylate tsopropanol Isopropyl acetate Isopropyl peroxydicarbonatc * Lubricating oil Methylisobutyl ketone Methane Methanol Methyl ethyl ketone Monoethanolamine Nonane(s) Poitassium hydrox- -- Sodium carbonate Sodium hydroxide Sfyiene Sulfuric add Teuaethylene glycol Toluene Triethylene glycol Vinyl acetate Vinyl chloride > t ucc 091492 / N 000 AN I :NNEPI044XA.92 L 072 Table 111. Frequencies of exposure and odds ratios for potential chemical exposures 073 Chemical 075 077 Work period Maintenance men excluded counted as exposed1 078 V 081 087 089 090 Carbon dioxide 0-14 15+ ever 109 111 112 131 ` 133 134 Diethyl sulfate > Diethylene glycol 0-14 15+ ever 0-14 15+ ever 153 Ethanol 155 156 0-14 15+ ever 175 Ethylene 177 178 0-14 15+ ever 197 Isopropanol 199 200 0-14 15+ ever 219 Methane 221 222 0-14 J5+ ever 241 Tetraethylene glycol 0-14 243 15+ 244 ever 263 Vinyl acetate 265 266 0-14 15+ - ever 285 Vinyl chloride 287 288 0-14 15+ ever E/UE 6/1 5/4 7/4 2/5 3/6 4/7 2/5 3/6 4/7 2/5 3/6 4/7 4/3 7/2 7/4 5/2 4/5 6/5 3/4 ' 6/3 6/5 2/5 3/6 4/7 5/2 5/4 6/5 3/4 3/6 4/7 4.80 1.35 2.14 4.43 4.87 2.10 (2)* (3)* (4)* 3.34 4.03 2.26 1.17 4.03 1.32 4.91 0.87 1.78 1.46 3.08 1.80 3.70 (3)* (4)* 3.10 2.74 3.30 1.16 0.81 1.13 90% Cl on RtM-H) 1.42-16.20 0.32-5.60 0.72-6.35 0.54-36.20 1,05-22.53 0.57-7.73 8.1S-* 95.5S-* 59.43-* 0.64-17.59 0.88-18.46 0.67-7.62 0.34-4.04 0.88-18.32 0.45-3.91 0.94-25.57 0.20-3.95 0.45-6.98 0.39-5.56 0.79-12.02 0.60-^5.43 0.57-23.87 20.24-* 3.01-* 0.80-12.05 0.57-13.20 0.84-12.88 0.29-4.58 0.20-3.76 0.31-4.04 E/UE R<m.h> 90% a on R<m-h> 12/1 12/3 15/2 8/5 9/6 11/6 8/5 9/6 11/6 8/5 9/6 11/6 10/3 13/2 14/3 11/2 10/5 13/4 $9/4 13/2 14/3 8/5 9/6 11/6 11/2 11/4 13/4 9/4 9/6 11/6 2.88 1.76 3.40 0.83-10.01 0.58-5.35 1.01-11.38 1.19 0.75 1.13 0.45-3.15 0.27-2.12 0.45-2.81 1.26 0.48-3.33 1.05 0.36-3.06 1.25 . 0.48-3.25 1.13 0.84 1.19 0.41-3.89 0.30-2.38 0.47-3.01 1.17 0.36-3.78 1.69 0.42-6.82 1.23 0.40-3.74 2.75 0.76 1.73 0.80-9.46 0.25-2.31 0.59-5.07 1.38 0.44-4.39 2.12 0.66-5.32 2.01 0.66-6.19 1.24 0.49-3.11 1.19 0.38-3.72 1.58 0.57-4.42 2.67 1.89 2.47 0.85-8.38 0.62-5.75 0.88-6.94 1.05 0.91 1.12 0.42-2.65 0.38-2.16 0.49-2.59 R<m-h> * Mantel-Haensrel odds ratio estimate: 90% Cl 90% confidence interval; *(N) infinite odds ratio, based on N tables suitable for analysis; E * exposed; UE unexposed. 1 Maintenance employees who also worked in other departments without exposure counted as unexposed. - 0-14 = work less than I5 years before death ofcase: 15+ work 15 or more years before death of case. Cases with work experience in both the 0- to 14-year and 15+ year time periods are counted in each group. i dn ir UCC 097493 - N 000 AN1:NNEP1044XA.9I V L 315 Table IV, Median months ofexposure to selected chemicals (15 yearsor more before doth 316 ofcase; employees with no exposure excluded) 317 Time in maintenance department 318 excluded counted as exposed 319 cases/conlrols - 21 cases/controls z` 324 325 326 327 328 329 330 331 332 333 Carbon dioxide Diethyl sul&te Diethyleneglycol Ethanol Ethylene Isopropanol Methane Tetraethylene glycol Vinyl acetStc Vinyl chloride 44/36 7/58 50/61.5 9/50 33/41 33/91 19/38 50/61.5 55/60.5 63/59 0.30 - 1.51 0.55 0.65 0.62 - 1.47 0.81 0.36 -- 0.42 0.24 45.5/39 50/80 65.5/80.5 69/36 87/59 55/57 36/47 81/84 63/84 88/82 1.14 0.11 0.46 0.63 0.36 0.29 -uo 0,77 0.35 0.80 374 The expected value of the sum is ni(ni+nj+iy2 with variance ni0](ni+n2+ IV12. 375 '[(observed mnk-sum)-(predicted rank-sum)]/(predicted variance); z > 1.96 implies p < 376 0.05. L 380 Table V. Distribution among cases and controls of community of residence 381 383 389 391 392 402 404 405 415 417 418 Community La Marque Texas City Galveston Work period1 0-14 15+ ever 0-14 15+ ever 0-14 15+ ever , Cases lived ever/never 9/8 9/8 12/5 5/12 4/13 6/11 3/14 7/10 7/10 R<m-h> 3.95 4.80 5.86 0.48 0.28 0.49 0.92 0.87 0.83 90% Cl on RflU-H) t 1.60-9.77 1.61-14.26 2.25-15.25 0.16-1.41 0.09-0.86 0.19-1.29 0.32-2.67 0.36-2.06 0.36-1.96 428 429 430 R<m.h) * Mantel-Haenszel odds ratio estimate*. 90% Cl * 90% confidence interval. 1 0-14 work less than 15 years before death ofcase; 15+ * work 15 or more years before death of case. i  L 434 435 / '\ Table VI. Unmatched odds ratios for combinations of exposure to selected substances and La Marque residence 436 Time Maintenance men 438 excluded counted as exposed 439 440 441 464 466 467 483 493 495 496 521 523 524 549 551 552 577 579 580 605 607 608 633 635 636 661 663 664 689 691 692 717 719 720 exp- Exp+ LaM- LaM(A) (B) Exp- Exp+ LaM+ LaM+ (O (D) E>y>- Exp+ LaM- UM(A) (B) Exp- Exp+ LaM+ LaM+ (C) (D) Carbon dioxide 0-14 154ever 1.00 7.11 1.00 2.54 LOO 3.67 3.20 4.71 8.57 32.00* _ (1.00)* 22.00 1.43 80.00* 1.00 1.78 --LlooJ- (L14)* (3.73)** 5.43 13.82* 2.33 17.50* Diethyl sulfate 0-14 15+ ever 1.00 4.89* 4.40* 0.00 1.00 3.67* 5.50* 3.67* 1.00 3.63 24.17* 5.80* Diethylene glycol 0-14 15+ ever 1.00 7.67* 1.00 inf. 1.00 3.78* 3.83* 0.00 3.43 16.00 7.56* 17.00* Ethanol 0-14 15+ ever 1.00 4.89* 4.40* 0.00 LOO 7.67* 4.60* 5.11* 1.00 4.29* 18.75* 7.50* Ethylene 0-14 15+ ever 1.00 - 1.00 0.72 (i.ooy 2.05 0.87 8.67 (1.08)* (4.88)** 7.50 30.00* Isopropanol 0-14 15+ ever 1.00 6.00 1.00 0.56 1.00 1.64 7.50 3.33* 11.50* 7.50* 3.00 9.20* Methane 0-14 15+ ever LOO 1.00 0.53 (1.00)* 3.17 0.71 inf. (1.22)* (info*-* 9.50* inf.* Tctraethylene glycol 0-14 15+ ever LOO 1.00 1.00 7.67* 7.67* 2.75 4.60* 3.29* 8.80* 0 15.33 11.00* Vinyl acetate 0-14 15+ ever 1.00 . 1.00 1.00 7vlt 0.67 2.36 6.40 0.89 7.80 16.00* 10.67* 17.33* Vinyl chloride 0-14 15+ ever 1.00 2.67 1.00 0 1.00 0.90 6.00 1.60 13.50* 0 4.00* 2.25 1.00 LOO LOO 1.81 0.36 1.33 8.40 6.25* 12.80* 4.31 4.17 7.00* LOO 1.00 1.00 1.69 0.48 0.78 5.79 3.75* 3.50* 4.91 7.00* 8.49* 1.00 1.69 1.00 0.38 1.00 1.33 8.10 5.20* 10.67* 4.15 4.67* 8.62* 1.00 - 1.00 0.81 (1.00)* 1.15 2.83 3.40 (5.90)* '(6.74)** 6.00 8.44* - 1.00 1.00 (LOO)* 0.28 1.02 (2.22)* 4.67* 5.40* (2.78)** 3.73 7.59* 1.00 - 1.00 0.59 (1.00)* 1.78 1.22 3.67 (3.26)* (8.29)** 5.25 14.54* 1.00 1.69 1.00 0.45 1.00 0.74 6.75 3.63* 3.78 4.50 6.77* 7.56* 4.00 1.00 (1.00)* 0.38 1.27 (1.90)* (3.03)** 1.24 7.09* 3.44* 11.63* 1.00 2.20 1.00 0.15* 1.00 1.20 9.00 2.25. 8.57* 6.00 4.50* 7.50* 745 746 747 748 749 750 751 752 V 753 Maintenance employees who also worked in other departments without exposure counted as unexposed. Except where otherwise indicated, all comparisons are to the uncxposed/never lived in La Marque category. Column B may be interpreted is the eflect ofchemical exposure alone, column C as the effect of La Marque residence alone, and column D as the effect of both. Exp- * bever exposed to the chemical; Exp+ * ever exposed to the chemical: LaM- never lived in La Marque. LaM+ ever lived in La Marque; inf. no controls in the category results in infinite odds ratio. Figures in parentheses are odds ratios with reference to never lived in La Marque/exposed. * Differs from column A; Fisher's exact test, p < 0.05. T * No cases in the never lived in La Marque/never exposed category result in infinite odds ratio. * J V 757 Fig. I. Map of La Marque addresses ever held by cases and controls. i, UCC 097495  'W / * * / i, Vcc 097496 7 / 4 ,'' * Circulate to: * 0 i Ptavwi tsjw 6. g,, n. . _________7 a 8 _. __________________ * % / UCC 097497