Document jg11E8EG1j04z34XxbROE7Mo5

757 759 760 761 762 763 764 765 Running title: Brain tiiomas in a Texas Chemical Plant Neuroepideniiotogy ECEIVEO AUG 2 4 1984 SCHNATTER Case-Control Study of Gliomas of the Brain among Workers Employed by a Texas City, Texas Chemical Plant Sanford S. Leffihgwetl, Richard Waxweiler, Victor AlexanderJioward R. Ludwig, Wiikam Haiperin National Institute for Occupational Safety and ^alth, Cioj^intti, Ohio. USA 759 Key Wards. Petrochemicals Brain tumors - Occupation Residence 77! H 772 H 773 774 775 776 777 H 778 779 Abstract. A Texas petrochemical plant had elevated standardized mortality ratios for neoplasms ofthe brainJ A casecontrol study examined possible associations between gliobu* of the brain and jib title, departmental employment bistory, chemical exposure his- tory 'geographic location within plant, dates of employment, and residence. The greatest apparent risks were associated with exposure to carbon dioxide, diethyl sulfate, diethylene glycol, ethanol, ethylene, isopropanol, methane, tetraethyknc glycol, and vinyl acetate; with first emptoymentjin the 1940s or early 1950s, and with residence in La Marque, Tex. No significant differences betweeu cases and controls were apparent in duration of expo* sure to any of these chemicals. 782 Introduction 734 In February (979, the National Institute for Occupational Safety and 735 Health (NIOSH) land OSHA, with the aid of the company management, 786 began an investigation of a duster of primary brain tumors at a chemicals 787 and plastics plant)in Texas City, Tex. Alexander et al. [1] 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 jhis plant from 1941 through 1977 have been reported [2, 791 3]. Findings included an overall standardized mortality ratio [SMR = 100 792 (observed/expeded)] for benign, malignant, and unspecified neoplasms of 793 the brain of 206l(p < 0.05). For those who worked more than 20 years at 794 the plant (i.e., wfio began work before 1957), the SMR was 377 (p < 0.05^ 795 [2]. No other careers were found significantly in excess ofexpected, and the 796 overall SMR wap not elevated. We here describe a nested case-control study 797 of primary braih tumor cases among the employees of that (riant 798 Austin and Schnatter [4] have recently published a parallel study which 799 showed no assejeiation between exposures in the plant and brain gliomas. 800 They used deceased employees whose deaths were known to the company 801 as controls for tjhe 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 group* including only hourly employees permitted further refine* 806 ment. These two studies are thus different enough to be complementary. 807 not duplicativi. s *8 8 .9 >.* d nr## if a ii * n 4s - 1/ 1 $8i1 J ^7 tings ?? i) UCC 071847 810 Methods i nd Materials 812 813 H 814 815 816 817 818 819 820 821 822 823 824 825 H 826 827 828 829 830 831 832 Case Identification A total of 23 possible cases were identified: the company documented 12 cases from death certificates] in their possession; lists of all adult males who were residents of sur* rounding counties and who died of malignant brain tumors between 1950 and 1977 were matched with company employment records, yielding 4 additional cases; another 3 cases became ill and died during the course of the study, and 4 additional deceased cases were found in the course of completing the cohort mortality study. We were able to obtain medical records fcr 20 of the possible cases and tissue specimens for 10; The Armed Forces Institute of Pathology (AFIP) reviewed the tissue specimens. Where different diagnoses were recorded for the same patient AFIP reviews were ranked first autopsy regions second, surgical pathology reporu third, diagnosis from the hospital chan fourth, ana (death certificate diagnosis last; the highest-ranked diagnosis was used for this study. [ Since gliomas are carcinomas, arising from ectodermal tissue of the neural crest while meningioffllas arise from mesodermal embryonic tissue, we followed the recommen dations of Schoenberg et al. (5], and limited consideration in this study to the 17 gliomas among the 23 farmer employees with death certificate diagnoses of brain tumor. This eliminated 1 case with a metastatic brain tumor from an unknown site, 1 who had been thought clinically to have a brain tumor but was found at autopsy to have a congenital fctalformation aim no tumor, and 4 meningiomas. A summary of the cases excluded and included is given in ubk I. 834 ' Selection o^Controi Subjects 835 For each case, a pool of matched potential controls was drawn from the cohort ofall 836 people ever employed at the plant. Matching criteria were: race and sex matched the case; 837 year of birth was within 3 years of the case's; date of first employment at the Texas City 838 plant for the control was before that of the case, but year of first employment at the Texas 839 City plant was riot earlier than 3 yean before the case's; the date the control was last 840 employed was lajler than the case's last date ofemployment; the control, if dead, must not 841 have died ofa malignancy. For each case, 6 controls were then drawn by random number 842 from the pool off employees meeting these criteria. No control was used for more than 1 843 case. Some casesjand controls had prior experience in refineries or chemical plants, but the 844 information available was, m our judgment, insufficient for analysis. 846 H 847 848 849 850 851 852 853 854 855 856 857 858 H 859 860 H 861 862 863 864 Data Coilettion For each< : and control, plant personnel completed coding sheets containing demo- graphic data, dat of each new job title or department code, job code, depanmem code, date ofeach layc f, date of final termination (if no longer employed at the plant), and vital status (when t). 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.1 produced, or redistributed in each department group. A 'department group* is an operational unit ofthe plant manufacturing related products and within which employees ofvenremained over fiririy 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 com pounds. we equated ihe presence of a chemical in a department with potential worker exposure. This assumption was clearly not always accurate, nor were exposures necessarily equal in two departments using the same chemical. UCC 071848 866 867 868 869 870 871 872 H8 H 8' H 6' 876 877 878 879 880 88! H 81 883 H 8! 88S 886 887 888 889 890 891 892 893 895 896 897 898 899 900 901 902 903 904 90S 906 Analysis For eachjob department, major department group, or chemical exposure common to at least 4 cases. ai| odds ratio was calculated and tested for possible statistical significance by MartteiandHctenszr!'s (6] procedure, using the matched data programs ofRothman and Boict (7). Analyses were conducted for periods less than IS yean before the death of the case, IS or more yean before the death of the case, and any time before the death of the case (a case exposed for greater than 13 years and dying soon after last exposure would be counted in all thrte periods). Since this approach is a multiple-significance testing tech nique which should lead by chance to the finding ofapproximately one `statistically signif icant' positive association, using a 90% (two-sided) confidence interval for every 20 inde pendent jobs, departments, or exposures considered, it is used here as an exploratory or hypothesis-generating mechanism; the probability values and confidence intervals cited throughout the paper are given only to show relative strength ofassociations. Only those portions ofthe controls* work experiences which occurred during the time the corTespondingjease was employed were considered in this analysis, since the matching criteria selected itrols with longer total work histones than the cases*, Duration of^ posure was examined for chemical exposures for which (a) the associa- tion with brain t ors readied statistical significance in the analyses described above or (b) previous trots' median m suggested a possible relationship. For each chemical, cases* and eoni ofpotential exposure 13 yean or more before death ofthe case were tabulated and a -sum test was performed [8]. Employees with no exposure were exduded. Workers in department nominally unexposed to a particular chemical could be exposed to toxic vapors or dusts from an adjacent department To assess this possibility, the worked by each subject in each department group were tabulated. showing which ient groups had about the expected 1:6 ratio of case to control- years, which groups had disproportionately more case-years, and which had fewer. This information was plotted on a map of the plant which was inspected for dusters. Son- Work Paaors 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 set vice was retained to determine past places ofresidence for the cases and controls and addi tional Information was obtained through review of medical records retained at the ph nt. Analyses were conducted for communities in which at least 3 cases had lived, using a livision of`ever lived' versus `never lived* in the community for periods 1S or more yean b :fore the death ofthe case, less than 13 yean before the death ofthe case, and any time befo e the death ofthe case. The analysis ofresidence used all addresses up to the date ofthecas *s death. A two-sided 90% confidence interval was calculated to display the strength ofass xnation. Addresses were also plotted on a map, which was inspected for further dues to th r epidemiology of this occurrence. 909 Results 911 Demograp ucs 912 Dale of fir t employment ofthe control subjects at the Texas City plant 913 averaged 18.0 months before that of the cases, and the control subjects were H 1 bom, on average, 4 months before the respective case, with standard devia H 1 tions 14.2 and $4 months, respectively. Only $ controls meeting the match 916 ing criteria weije available for one of the cases. UCC 071849 918 919 N 20 N 21 922 H 23 N 24 N 25 926 H 27 928 929 H 30 931 932 933 934 935 936 937 938 H 39 940 941 942 943 944 945 946 947 948 949 H 50 951 952 953 In-Plant Work History `Operator' was the only job code represented by 4 or more cases: the Mantei-Haenszel odds ratio for operators was 0.54, with ^Ji.h = 1.84 (not statistically!. There was no apparent commonality between the departments in which these operators had worked. When analyzed by department codes, only the maintenance depart ment had 4 or more cases; the Mantel-Haenszel odds ratio was 0.32 with ft-H- 1.37 (jiot statistically]. Grouping the department codes into major departments yielded no new groups of 4 or more cases. When casles and controls were analyzed by potential chemical expo sures, a new problem became evident: maintenance men moved throughout the plant and were exposed to many different agents in an irregular manner. Accordingly, we have examined the data in two ways: in the first, mainte nance men wire considered to have been exposed to every agent in the plant; in the second, they were excluded from analysis. The first method may be close) to reality; indeed, maintenance men may have received higher exposures to toxic chemicals than operators since, in maintenance work, they must open pipes, reaction vessels, and pumps. On the other hand, the assumption of exposure for all maintenance men, whether cases br controls, rrtay tend to obscure an elevated odds ratio that might be present ifexact data were available. Ofthe 505 chemicals reviewed, table II lists all chemicals to which at least 4 cases were exposed (excluding main tenance jobs). I Statistics for distribution of `exposures' among cases and controls are presented in table in. The tables include the chemicals to which 4 or more cases were exposed and which showed the strongest positive association with brain tulnore, plus vinyl chloride. Vinyl chloride monomer was included since it has previously been associated with brain tumor excess [9-111. Results of analyses by duration of exposure are summarized in table IV. No statistically significant differences between cases and controls were apparent! in duration of exposure to any chemical. In the mapping analysis of work locations within the plant, no signifi cant clustering of areas with proportionately more case-years than controlyears was detected. Analysis of work locations of cases and controls within 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 in the nearby town ofLa Marque, but neither exact dates of residence in each community nor street addresses could be determined. Complete listings of at least the community of residence wjere available for 93 of the 101 controls; partial listings, often inexplicit as tp the exact date of moving from one community to another, were availablq for another 7 controls. No information at all was available for the residence ol^bontrol. In most instances, streets or streets and num bers could be determined, but there were many instances where informants could no longer remember street addresses of 40 years ago. IX Jl tJ (2) UCC 071850 966 Table V Shows the distribution of addresses among cases and controls 7 (note: some subjects appear in both the `less than 15 years' and 'greater than 968 15 years' columns). The odds ratio for Texas City difTered markedly from 1, H 69 while that forlGalveston is essentially equal to 1. La Marque had an appar- H 7Q ent excess of oases over controls (maximum odds ratio * 5.86). It is a resi- 97j dermal community, without heavy industry, and lies southwest of Texas H 72 City, west of me plant, and north of Galveston. A chemical dump, estab973 lished in 1959 and listed by the Environmental Protection Agency as a H 74 high-priority site for emergency cleanup, is located at the southeast extrem975 ity of La Marque. Vinyl chloride levels as high as 161 parts per billion have 976 been measured at the fence line of the dump [12]. Figure 1 shows that the 977 known addresses for the cases who lived in La Marque appear to cluster 97g toward the southern and western parts ofthe city, not adjacent to either the 979 plant or dump nor downwind from them. Drinking water for La Marque 980 and Texas City comes from deep wells, tapping the same stratum, while 981 water for Galveston comes from the Brazos River. The average length of 982 residence in La Marque (excluding those who never lived there) was 12.4 H 85 years for casesl and 16.3 years for controls; this difference was not statisii- 984 cally significant. 985 Highland Bayou, a slow-moving stream draining into Galveston Bay, 986 runs along the southwestern and southern edge ofLa Marque, upwind from 987 the community. In view of the large number of publications associating 9gg glioblastomas with viral agents [13-20], a mosquito-bome virus seemed an 989 interesting etiological hypothesis, as did kerosene and various insecticides 990 used to control mosquitos during and after World War 11. 991 To separate the effects of exposures to chemicals and residence in La 992 Marque, we classified subjects into 4 strata for each chemical according to H 93 history of exposure to that chemical (exp+ or exp-) and history of LaMar994 que residence (jLaM+ or LaM-). Each of 3 strata (exp+LaM+, exp-LaM+, 995 and exp+LaM-Q was compared to cases and controls who had neither risk 996 factor (exp-LaM-); i.e^ three 2X2 tables were analyzed for each chemical fvj 97 and the odds ratios were compared, as suggested by Kieinbaum 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 IV 00 resulted. Results are shown in table VI. The odds ratios generally arc greater 001 for La Marque jresidence without chemical exposure than for exposure to 002 individual chemicals without La Marque residence and often are quite a bit 003 greater for exposure to both risk factors than for either one alone. During 004 the period longer than 15 years before the death of the case for analyses in H 05 which mainteiufnce men were excluded, only ethanol and di- and tetrJTthy- 006 lene glycol show a stronger association with disease than does La Marque 007 residence. j 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 On 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)] J J UCC 071851 020 Discussion 022 The greatest apparent risks were associated with exposure to carbon 023 dioxide, diethyl sulfate, diethylene glycol, ethanol, ethylene, isopropanol, 024 methane, tetraeihylene 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 teal associations found may need further study, but are not convincing evi- 027 dence, particularly in view ofAustin 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 sums likely to be experienced by workers would have virtually no effect on 03 5 normal physioldgic levels, eliminates CO2 from further consideration. Its 036 appearance on the list serves to illustrate the pitfalls of multiple significance H 37 testing mentioned above and to inject a note of caution in forming condu038 sions based on other associations in this report. Methane, with 6 cases 039 potentially exposed (excluding maintenance men), is similarly unlikely to H 40 be present in ariounts capable of increasing exposure markedly over back- 04 1 ground levels produced by intestinal flora. 042 We were udable to find reports ofcarcinogenesis or mutagenesis testing 043 -on tetraeihylene glycol. Diethylene glycol was found to cause bladder stones 044 and tumors in pne test using rats [23], but has not been carcinogenic or 043 mutagenic in other experiments [24, 25]. Excluding maintenance men, a 046 total of 4 cases (^finitely worked in departments 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 findingimay be the result of multiple significance testing. 050 Diethyl sulfate is considered a carcinogen and has caused brain tumors 031 in experimental animals [26]. With regard to other chemicals, a statistically 052 significant exceis of brain tumors was observed in a British isopropanol 053 plant, although I the numbers were very small [27]. Several other cancers 054 have been associated with isopropanol exposure, although pure isopropanol 053 is not usually considered carcinogenic [28-301- Ethylene, like vinyl acetate 056 and vinyl chloride, has an unsaturated two-carbon moiety. Although both H 57 ethylene and vinyl chloride are metabolized through a highly reactive epox053 ide stage whichjmay alkylate organic compounds [31, 32], ethylene is not 059 mutagenic in Ames tests [N/osh, 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 an vinyl acetate; it is not mutagenic in bacterial assay (34, H 62 35]. Information on association with length ofexposure, latency, and num063 ber of cases who could be attributed to the chemical if it were a brain H 64 carcinogen does not point clearly toward any of these chemicals but obser- H 65 vation of other clusters or cohorts might indicate iljt one of them is danger- 066 ous. H 67 While som: of the associations found could be considered weak evi- 068 dence of carcinogenicity, none was conclusive. Thera are wide confidence 069 intervals around all of the odds ratios given; therefore, differences between 070 odds ratios sho ild be interpreted cautiously. 071 It is possib e that a critical exposure was more general than implied by 072 the department group analysis used here, and that use of in-plant controls 073 constituted ove -matching which might have obscured a significant finding. N 74 We know of no atisfactory way to test this possibility within the confines of 075 the present stuc v. I ha UCC 071852 H 76 ms* associated wur .**arque re*- iwL man uiaidiiU* fl 77 dated with the [chemicals studied. La Marque and Texas City share a com' 078 mon water sou rce, but La Marque has a higher ratio of cases to controls '79 than Texas Cil y, therefore a water-borne environmental carcinogen (36] 080 081 H 82 083 seems unlikely. Since there are no major chemical or other industries upwind from tie community, airborne industrial carcinogens do not seem to be a likely explanation for the association observed. (The wind is domi nantly out of tne south-southeast.) The cases' shorter average duration of 084 residence in La Marque argues against a causal association with residence. 083 From the comparison of crude death rates for La Marque and 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 pait, 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 and is under sti^dy by NIOSH. Examination ofthe residence histones ofthe 091 cases who worked at that refinery showed that only 3 of 8 had lived in La 092 Marque. 093 The type c|f mosquito which constitutes the greatest problem in the La 094 Marque area his a range of 25-50 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 jneeded to understand it. 101 Greenwaid et al. [39] have suggested that superior medical care may 102 lead to more fijequent diagnoses of brain tumors among employed workers 103 with good medical insurance programs. They presented evidence of more 104 scj^sticated aiagnostic methods in Eastman Kodak employees with brain 103 tumors. Although it is reasonable to suppose such sophistication would lead 106 to 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 110 the Mayo Giijic 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 % of Rochester decedents had 114 autopsies, compared to an estimated 38% in Connecticut; in Rochester, US 116 H 17 H 18 H 19 60% of meningiomas were found at autopsy, compared to only 17% of glioblastomas. None of the cases in this series were first diagnosed at autopsy and gliomas predominated in this group (85 vs. 40.3% in Roches ter). Our impression, from the medical records examined, is that the diag noses in this case series did not hinge on either multiple ot highly sophisti H 20 cated tests, tax we cannot determine the extent to which diagnostic sensi 121 tivity bias might be a factor in this cluster. 124 Acknowledgments 125 H 126 127 128 129 130 131 132 We wish to|thank the Union Carbide Corporation for freely opening their records to us and in particular Mr. Damon Engle. Plant Manager. Dr. David Glenn. Gulf(Toast Med ical Director. Mjs. Dorothy Hewn, Director of Personnel Relations; Mr. Robert Frantz. Engineer, and Mb. Ferihan Yaiankaya. Industrial Hygienist. We are also indebted to the Texas Bureau oflViul Statistics and to M.D. Anderson Hospital and Tumor Institute for their help in cascifinding and vital status ascertainment. Messrs. Richard Miller. Ben Bare. and Davis Larnrlof the OSHA Houston South Area Office, and Dr.J. William Lloyd ofthe OSHA Headquarters Staff provided invaluable advice throughout the study. tU VCC0718S3 References' I Alexander. V.; Leffingwcll. S3.; Lloyd. J.W.; Waxweiler. RJ.; Miller. R.L.: Brain cancers in petrochemical workers - A case series report Am. J. ind. Med. /: 115*123 (1980). 2 Waxweiler. i|j Alexander, V.; LefTinfwell, S3.; Haring, M.; Lloyd. J.W.: Mortality from brain tfcmor and other causes in a cohort of petrochemical workers. J. natn. Cancer Inst. JO: 75-81 (1983). 3 Austin. S.G.: Schnatter, A.R.: A cohort mortality study of petrochemical workers. J. occup. Med. j?5: 304-312 (1983). 4 Austin. 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N.S.: Mortality ofworkers on an isopropyl alcohol plant and two MEK dewaxing plants. Br. J. ind. Med. J7:85-89 (1980). Enteriine. fLE; Uiis, Alexander, V.; Mtltoni, C.: Importance ofsequential expo* sure in the production ofepichlorohydrin and isopropanol. Ann. N.Y. Acad. Sci. 381: 344-549 (1^82). Weil, CS4 Smyth. H.F.; Nile, T.W.: Quest for a suspected industrial carcinogen. Arehs ind. Hyg- occup. Hlth 3:535-547 (1952). Hueper, WiC.: Occupational and environmental cancers of the respiratory system. Specific occupational cancers and their environmental counterparts (Springer, New York 1966i Ehrenberg. |l~; Osterman-Golkar. S.; Segerback, D.: Svennson, K_; Calteman, CJ.: Alkylation of haemoglobin after metabolic conversion of etbene to ethene oxide in vivo. MutaL Res. 43: 175-184 (1977). Green, T.; Hathaway, D.E.: The biological fate of vinyl chloride in relation to its oncogenicity. Chem.-biol. Interactions II: 545-562 (1975). Gralla, EJ.: A twenty-four month inhalation toxicology study in Fischer-344 rats exposed toi atmospheric ethylene (Chemical Industry Institute of Toxicology, Re search Triangle Park 1980). Banach. Hi Momesano, R.: Prescreening ofenvironmental and industrial chemicals ina senes fshort-term tests for the detection of potential carcinogens. Comm. Eur. Communi (Rep.) EUR: 1SS EUR 6388, Environ. Res. Programme, pp. 269-373 (1980). Ujinsky, Andrews, A.W.: Mutagenicity ofvinyl compounds in Salmonella lyphimurium. ttog. Carrinof. Mutagen. 1:259-267 (1980). Cantor, K. Hoover, R.; Mason, J.T.; McCabe, LJ.: Associations of Cancer mor tality with! halomethanes in drinking water. J. natn. Cancer Inst. 61: 979-985 (1978). j Mix, D.: Personal communication. Musicco, Pi.: Filippini, G.: Bordo. B.M.: Melotto, A.: Morello, G.; Benino, F.: Glio mas and occupational exposure to carcinogens: case-control study. Am. J. Epidem. 116: 782-^89 (1982). Greenwakj. P.; Friedlander. B.R.: Lawrence. CX; Heame, T.; Earle. K.: Diagnostic sensitivity bias - an epidemiologic explanation for an apparent brain tumor excess. J. occup. Mefl 23:690-694 (1981). Gann. P.; jRosenman. K.D.: Conclusions questioned in brain tumor excess study. J. 1. 24:428 (1982). P.; Friedlander. B.R.; Lawrence. C.E; Heame. T.: Earle. K.: Author's occup. Med. 24:428-432 (1982). B.S.: Christine, B.W.; Whisnant. J.P.: The resolution ofdiscrepancies in the reported incidence of primary brain tumors. Neurology 28: 817-823 (1978). 243 Sanford S! Leffingwetl. MD. MPH. 244 National institute for Occupational Safety and Health. 245 4676 Colombia Parkway.^ 246 .Cincinnati. OH 45226 (USA)J* d UCC 071855 N 000 AN l :NNEPI044XA.96 L 001 Table I. Cases fr m cohort study included in and excluded from case-control study 002 Diagnosis Included Excluded 005 Gliomas 007 Glioblastoma tnultiforme (includes of astrocytoma 008 grades III and IV) 010 Thalamic gliol destoma suspected clinically; no tumor 011 in biopsy of abnormal appearing area of brain cortex 013 Pituitary aden xarcinoma suspected clinically; radio- 014 therapy foil* wed by proven glioblastoma 12 years later 016 Astrocytoma | radell 018 Metastatic tumo r, unknown primary 020 Brain tumor sus sected clinically, not found at autopsy 022 Meningioma, mi ilignant 024 .Meningioma, benign 026 Subtotal 029 Total 17 14 1 1 1 17 22 l 1 3 1 6 L 034 Table II. Chemicals to which four or more cases were exposed 035 Acetaldehyde 036 Acetic acid 037 Acetone 038 Carbon dioxide 039 Diethanolamine 040 Diethyl sulfate 041 Diethylene glyo >1 042 Ethanol 043 Ethylene 044 Ethylene dichlofkle 045 Ethylene glycor 068 Hydrochloric acid Hydroxypropyl acrylate Isopropanol Isopropyl acetate Isopropyl peroxydicarbonate Lubricating oil Methylisobutyl ketone Methane Methanol Methyl ethyl ketone MonoethanoUmme Nonane(s) Potassium hydrox- HdeJ ' ' Sodium carbonate Sodium hydroxide Styrene Sulfuric acid Tetraethylene glycol Toluene Triethylene glycol Vinyl acetate UCC 071856 N 000 ANI:NNEP1044X^92 L 072 073 075 077 078 V 081 087 089 090 Table HI. Frequencies of exposure and odds ntiOS for potential chemical exposures -- ........-- i> Chemical ! I i Work periof Maintenance men excluded counted as exposed1 j E/UE R<m-h> 90% a on E/UE 90% Cl on R<m-w R<M4i> Carbon dioxide| 1 0-14 15+ ever 6/1 4.80 1.42-16.20 5/4 1.35 0.32-5.60 7/4 2.14 0.72-6.35 12/1 12/3 15/2 2.B8 1.76 3.40 0.83-10.01 0.58-5.35 LOl-i 1.38 109 in 112 131 * 133 134 153 155 156 175 177 178 197 199 200 219 221 222 Diethyl sulfate JI i Diethylene cited 1 Ethanol i1 I ! fEthylene li J Isopropand | . I. Methane H ! 0-14 15+ ever 0-14 15+ ever 0-14 15+ ever 0-14 15+ ever 0-24 15+ ever 0-14 15+ ever 2/5 3/6 4/7 2/5 3/6 4/7 2/5 3/6 4/7 4/3 . 7/2 7/4 S/2 4/5 6/5 3/4 6/3 6/5 4.43 4.87 2.10 (2)* or (4)* 3J4 4.03 2.26 1.17 4.03 1.32 4.91 0.87 1.7$ 1.46 3.08 1.80 0.54-36.20 1.05-22.53 0.57-7.73 8.1S-* 95.55.* 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 0.4S-6.98 0.39-5.56 0.79-12.02 0.60-5.43 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 1.19 0.75 1.13 1.26 1.05 1.25 1.13 0.84 1.19 1.17 1.69 1.23 2.75 0.76 1.73 1.38 2.12 2.01 0.45-3.15 0.27-2.12 0.45-2.81 0.48-3.33 0.36-3.06 0.48-3.25 0.41-3.89 0.30-2.38 0.47-3.01 0.36-3.78 0.42-6.82 0.40-3.74 0.80-9.46 0.25-2.3! 0.59-5.07 0.44-4.39 0.66-5.32 0.66-6.19 241 243 244 Teuaethylene glycol J 0-14 15+ ever 2/5 3.70 0.57-23.87 3/6 (3)# 20.24-* 4/7 (4)# 3.0I-* 8/5 1.24 0.49-3.11 9/6 1.19 0.38-3.72 lt/6 1.58 0.57-4.42 T263 Vinyl ackate 265 1266 7285 Vinvl chloride 287 288 I 0-14 15+ ever 0-14 (5+ ever 5/2 3.10 0.80-12.05 5/4 2.74 0.57-13.20 6/5 3.30 0.84-12.88 3/4 1.16 0.29-4.58 3/6 0.87 0.20-3.76 4/7 1.13 0.31-4.04 11/2 11/4 13/4 9/4 9/6 11/6 2.67 1.89 2.47 1.05 0.91 1.12 0.85-8.38 0.62-5.75 0 88-6.94 0.42-2.65 0.38-2.16 0.49-2.59 N 307 R^m.H! * Mamd-Haenswl odds ratio estimate; 90% Cl * 90% confidence interval; * (N) * infinite odds ratio. V 308 based|on N tables suitable for analysis: E * exposed; UE * unexposed. 309 ' Maintenance employees who also worked in other departments without exposure counted as unexposed. 310 - 0-14 = work less than IS years before death ofcase; 15+ work 15 or more years before death ofcase. Cases 311 with Work experience in both the 0- to 14-year and 15+ year time periods are counted in each group. / / Vcc 071857 N 000 ANI:NNEPI044kA.9l L 315 Table IV. Median! months ofexposure to selected chemicals (15 yean or more before death 316 ofease; employee! with no exposure excluded) ' 1317 Time in maintenance department 318 counted is exposed 319 cases/controls -z* cases/controls X* 324 Carbon dioxide 325 Diethyl sullate 326 Diethylene glycol 32? Ethanol 328 Ethylene 329 Isopropanol 330 Methane 331 332 Teuaetbylene Vinyl acetate glyctIT 333 Vinyl chloride 44/36 7/58 50/61.5 9/50 33/41 33/91 19/38 50/61.5 35/60.5 63/59 0.30 1.51 0.35 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 55/37 36/47 81/84 63/84 88/82 1.14 0.11 0.46 0.63 0.36 0.29 -1.10 0.77 0,35 0.80 374 The expected value of the sum is ni(ni+nj+iy2 with variance *n|R2<Di+n2+ I)/I2. 375 [(observed rankestdm)--(predicted rank>sufn)]/(predicted variance); z > 1.96 implies p < 376 0.05. L 380 Table V. Distributio s 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* j ever 0-14 1 i5* 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 Ro**H> 3.95 4.80 5.86 0.48 0.28 0.49 0.92 0.87 0.83 90% Cl on R<m-h 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 Mantel-Haeitszel odds ratio estimate; 90% Ci 90% confidence interval. 429 1 0-14 * work less th*h 15 yean before death ofcase; 15+ * work IS or more years before 430 death of case. UCC 071858 < L*i4 Table VI. Unmatched odds ratios for combinations of exposure to selected substances and La Marque resi 4j. dence 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 71? 719 720 Carbon dioxide 0-14 15+ ever Diethyl sul&te 0-14 15+ ever Diethylene glycol 0-14 154ever Ethanol 0-14 154ever Ethylene * 0-14 154ever Isopropanol 0-14 15+ ever Methane 0-14 15+ ever Tetraeihylene giyci 1 0-14 15+ ever Vinyl acetate 0-14 15+ ever Vinyl chloride 0-14 154ever exp- Exp+ LaM- LaM<A) (B) Exp- Exp+ LaM+ LaM+ (O (D) Exp- Exp+ LaM-- LaM- (A) (B) Exp> Exp* LaM* LaM* <C) (D> 1.00 1.00 1.00 7.11 2.54 3.67 3.20 4.71 8.57 32.00* 22.00 10.00* 1.00 1.00 1.00 4.89* 3.67* 3.63 4.40* 5.50* 24.17* 0.00 3.67* 5.80* LOO 7.67* LOO inf. 1.00 3.78* 3.83* OX 3.43 16.00 7.56* 17.00* LOO 1.00 LOO 4.89* 7.67* 4.29" 4.40* 4.60* 18.75* OX 5.11* 7.50* LOO - LOO 0.72 (LOO)* 2.05 0.87 8.67 (1.08)* <4J8)** 7.50 30.00* LOO 1.00 LOO 6.00 0.56 L64 7.50 3.33* 11.50* 7.50* 3.00 9.20* LOO - LOO 0.53 (LOO)* 3.17 0.71 inf. (1.22)* (W>* 9.50* inf.* LOO 7.67* LOO 7.67* LOO 2.75 4.60* 3.29* 8.80* 0 15.33 11.00* LOO 7.11 LOO 0.67 LOO 2.36 6.40 0.89 7.80 16.00* 10.67* 17.33* 1.00 LOO LOO 2.67 0 0.90 6.00 1.60 13.50* 0 4.00* 2-25 (LX)* 1.43 LOO 1.78 1.00 r (L14)* (3-?3>** 5.43 13.82* 2J3 17.50* 1.00 1.81 LOO 0.36 1.00 1.33 8.40 6.25* 12.80* 4.31 4.17 7.00* IX LOO IX 1.69 0.48 0.78 5.79 3.75* 3.50* 4.91 7.00* 8.49* LOO LOO IX 1.69 0.38 U3 8.10 5.20* 10.67* 4.15 4.67* 8.62* IX LOO 1.00 LOO 0.81 (LX)* L15 (LX)* 0.28 L02 2.83 (5.90)* 6X (122+ 4.67* 5.40* 3.40 (6.74)** 8.44* (2.78)** 3.73 7.59* LOO IX 0.59 (LX)* 1.78 1.22 3.67 (3.26)* (8.29)** 5.25 14.54* IX IX LOO LOO IX 1.69 0.45 0.74 (LX)* 0J8 1.27 6.75 3.63* 3.78 (1.90)* 1.24 3.44* 4.50 6.77* 7.56* (3.03)** 7.09* 11-63* IX IX IX 2.20 0.15* 1.20 9X 2.25 8.57* 6X 4.50* 7.50* 745 746 747 748 749 750 751 752 V 753 Maintenance empty?yces who also worked in other departments without exposure counted as unexposed. Except where oither wise indicated, all comparisons are to the unexposed/never lived in La Marque category, Column B may be nterprvted as the effect ofchemical exposure alone, column C as the effect of La Marque residence alone, a;rid column D as the effect of both. Exp-. never exposed to the chemical; Exp* * ever exposed to the chcmikal: LaM- never lived in La- Marque: LaM+ * ever lived in La Marque; inf. no controls in the catetory ri esults in infinite odds ratio. Figures in parentheses are odds ratios with reference to never lived in La 44arque/exposed. Differs from column A; Fisher's exact test, p < 0.05. * No cases in the liever lived in La Marque/never exposed category result in infinite odds ratio. V 757 Fig. I. Map < fLa Marque addresses ever held by cases and controls. UCC 071859 UCC 071860 WASHINGTON, D. C- OFFIfE Andrews & Kurth 1747 PENNSYLVANIA AVE..N.W. WASHINGTON, o-c.aooqe (2021 861-7400 Andrews & Kurth ATTORN EYS TEXAS COMMERCE TOWER HOUSTON, TEXAS 77002 (713) 220-4200 TELECOPIER: (713) 220-4895 TELEX: 79- 120 0 August 27, 1984 DALLAS OFFICE Andrews, Kurth & Ritchie MOO RERUBLIC8ANK BUILCHNG DALLAS, TEXAS 75201 I2IA) 742-6285 CERTIFIED MAIL Mr. F. Walter Conrad Baker <3c Bott4 3000 One Shell Plaza Houston, Texjs 77002 r4: No. G-83-48 (Consolidated); Dorothy Bell, Individually and as I Executrix of the Estate of Dewey Bell, Deceased and Thelma O. I Kingsbury, Individually and as Representative of the Estate of I Thomas Page Kingsbury, Deceased vs. Stauffer Chemical Company, I et al.; In the United States District Court for the Southern District of Texas, Galveston Division Dear Walter: Th is letter is to confirm our conversation of August 24th, in which I agreed to suspend yo jr need to answer our discovery until such a time as we would later request, and in which you agreed to supply us, as soon as possible, with all information with regard to the purchase of any vinyl chloride. As you know, it is our hope that we will be able tc show that Stauffer Chemical Company did not supply any vinyl chloride to the plant iij question. Since we have a November discovery cut off, we shall need this information by at least October 1, 1984. Any help in this regard would be appreciated. Yours truly, /] \ 169/lap Andrew S. Hanen UCC 071861