Document Y2LD5bE5e4DgzVJa87gXBLNn

1 DRAFT VI Brain Cancer In Petrochemical Workers - A Case Series Report Nineteen primary brain cancer deaths have been found among workers at one United States petrochemical plant. We believe this is the largest single series of presumably occupationally-related brain cancers reported in the medical literature. In November, 1978, the Occupational Safety and Health Administration (OSHA), the Federal occupational health enforcement agency of the U.S. Department of Labor, received an employee complaint that work-related chemical exposures might have caused brain tumors in fellow workers as well as his own recently diagnosed brain cancer. OSHA's Office in Houston, Texas began an investigation of brain cancer mortality at the employee's worksite, a moderate-sized petrochemical production facility in Texas City, located In Galveston County south of Houston. Workers, family members and surviving relatives, union officials, local physicians and hospital staff, Texas state health officials and company personnel were interviewed. Four primary brain tumor deaths were discovered among former employees In this way. It is ironic that the worker who filed the original complaint with OSHA was found to have a metastatic carcinoma to the brain, and is not counted amonq the cases. The plant physician subsequently reviewed death information maintained by the medical department, primarily covering workers who died while employed and who by virtue of 15 years of company service were eligible for death benefits. Ten deaths from primary brain cancer were identified. These ten DO NOT COPY OK OUOTE -2- DRAFT VI included the four previously found. OSHA then requested technical as sistance from the National Institute for Occupational Safety and Health (NIOSH), its companion research agency in the U.S. Department of Health, Education, and Welfare. In February,.1979 OSHA, NIOSH, and the company established a collaborative study plan to Investigate the apparent excess of brain cancers. An his torical prospective cohort mortality study was begun to determine the Standardized Mortality Ratio (SMR) for brain cancer, and whether there exists any other unusual mortality pattern. Also Included within the cohort study Is a case-control study of all primary brain cancer cases to estab lish whether a particular job or chemical exposure at the plant Is as$o-~' dated with an excess risk of brain cancer. A reference neuropathology laboratory has agreed to examine autopsy and surgical pathology specimens to provide histologic confirmation of the cause of death. Each of these studies is well underway, and results are expected within a few months. * An experimental case-finding technique was added to the study design to provide an early estimate of the extent of the problem. A computerassisted search was conducted of Texas Bureau of Vital Statistics data maintained by the M.D. Anderson Tumor Institute Department of Epidemio logy. Since company records showed that 99% of plant employees reside in Galveston, Harris and Brazoria counties, a list of all primary brain cancer deaths among males more than twenty years of age from 1950 through 1977 was obtained for these three counties. This list of 732 primary brain ucc 048396 DO NOT COPY OR QUOTE 3 ** DRAFT VI cancer deaths was matched against company personnel files. Four additional confirmed cases resulted. Further investigation of company records re* vealed two more cases. Three other employees became ill during the pre liminary period of the study. All cases were deceased as of March, 1980. The current total of 19 cases is the subject of this case series report. Work history data for the 19 cases are provided in Table 1. The average age at death for the cases was 52; the youngest died at age 30, and there were four deaths after age 60. Over half the deaths occurred between ages 50 and 59. The age distribution observed in this series does not differ significantly from that reported In other series. Total length of employment at the plant ranged from 1 month to slightly more than 35 years, with a median value of 20 years. Two cases had short exposure periods of 38 and 2S days respectively. Median length of employ ment excluding these two cases was 22 years. The interval from first employment to death, which provides an estimate of latency, varied from as few as 3 1/2 years to nearly 36 years, with a median of 24 ye'ars. The median values for exposure and latency period in this series are typical of those found for other tumor types In occupational cancer investigations and are consistent with a hypothesis of occupational etiology resulting from chemical exposures. No particular trend or clustering by hire date among the cases has been Identified as compared to the general plant population. One case was V grams' ucc 048397 DO NOT COPY OR QUOTE -4- DRAFT VI hired in Tate 1940 as part of a small plant start-up crew. Three rare were hired in 1941 during the first year of plant operation, and the others at fairly regular intervals until the last group of four started work during 1953. The first death occurred in 1956, followed by five others during the 1960's. Twelve of the deaths occurred after 1970, three of them during the past year. No established pattern Is evident from the observed years of death, but there is no evidence that the rate of appearance of cases is declining. The plant has a current workforce of slightly more than 2,200, Including nearly 1,500 hourly and production employees. The average age Is 44, and approximately 1,050 current employees have 25 or moreJyears of company service. Since the plant began operation In 1941, there have been a total of 8,850 employees. These include 6,802 white males, 884 black males, 1,083 white females, and 81 black females through December, 1979. The distribution by county of residence for current workers is provided in Table 2. The plant also engages a temporary Independent contractor work force of 100-250 daily, mostly for construction jobs. Unfortunately, no employment records are available for this group. Domoqraphic and cause of death data from the death certificates are pro vided in Table 3. All cases occurred among male employees, 18 whites and 1 black. The mortality rate for primary brain cancer In Texas among black males Is about one-half that for white males.^ However, very little' can be said regarding the racial distribution of cases, since it appears PHESHKb? n "ri raw UCC 048398 DO NOT COPY OR QUOTE -5- DRAFT VI that increased numbers of black employees have been employed at the plant only in recent years. All but one of the cases were native-born Americans; the lone exception was Norwegian.^ The great majority of the cases were born in Texas, two were from Louisiana, and one each was from Massachusetts, New Mexico, and Oklahoma. None of the U.S. states of origin have a particularly high risk for brain cancer, compared to the U.S. national average. There Is pre sently no information available about the age of the cases when they moved to Texas, or where else they may have lived. Sixteen of the cases were Galveston County res1dents_.at the time of death; the other three were from Harris County. The possibility of an environ mental etiology related to Galveston County was considered. County-wide data from the National Cancer Institute on the brain cancer mortality rates for Harris, Galveston, and Brazoria Counties from 1950-1969 are In the mid-range for Texas and U.S. national values as shown In Table 4. A survey made by the Texas State Department of Health for 1977 showed that the Galveston County brain cancer crude mortality rate was 3.6/100,000. There \ J 1$ no evidence from these data that local environmental factors outside the plant are responsible for the apparent excess of brain cancer. To obtain an Initial estimate of the brain cancer risk, brain cancer deaths among adult white males In Galveston County were analyzed using the list described previously. A total of 54 primary brain cancer deaths occurred In the county from 1962 through 1977. To establish a rough ucc 048399 00 NOT COPY OR QUOTE -6- DRAFT VI comparison, information from the Health Services Administration on county population characteristics was used.^ In 1970 Galveston County was 68% white, and 62% of the population were between the ages of 14 and 64. A 1970 county population estimate was 170,000 of whom 49% were males.^ Thus, the white male population of employment age at risk during 1962-1977 was somewhat less than 38,000; the plant white male population was about 1,800 or about 5% of the county total. Yet during this period, 11 of 54 brain tumor deaths among county residents occurred in plant employees, nearly 20% of the total. This suggests an approximate plant-wide risk of about four-fold. The underlying causes of death as recorded on the death certificates are listed in Table 2. Nine cases of glioblastoma multiforme were recorded directly on the certificate. Further investigation of hospital and physi cians' records provided evidence that there were six additional cases of glioblastoma multiforme among the total of 19. According to these records one case also was reported to be a metastatic lesion to the cerebellum. Preliminary medical evidence thus suggests that 81% (15/19) of the tumors were glioblastomas. Because this type of tumor usually accounts for 40-55% of deaths in reported brain cancer series, this would Indicate an excess of glioblastoma multlforme among these cases.{1237,8) -j^e difficulty of precise neuropathological diagnosis for brain cancer is recognized, and the pathology review is expected to better define this observation. Thr plant 1$ a diversified petrochemical manufacturing facility with a la ce number of major product lines, including ethylene, butadiene, naphtha, DO NOT COPY OR QUOTE -7- DRAFT VI ethylene dichloride, diethyl sulfate, glycols, aldehydes, acetates, alcohols, amines, organic acids, and plastics and resins (polyethylene, vinyl chloridevinyl acetate copolymers, phenol-formaldehyde resin). Review of the plant's chemical Inventory reveals the presence of at least 11 recognized or suspect carcinogens In significant quantities as raw materials, reaction by-products, or manufactured compounds. These are shown in Table 5. Careful preliminary examination of the work histories of affected employees does not yet estab lish any common job title, department code, or chemical exposure. Eight of the men were chemical operators In production departments but they were spread throughout the plant, and worked on different chemical processes. Six others were maintenance workers who my have had tht opportunity for plant wide exposures over the years. Two worked In the chemical shipping depart ment as weighmasters with likely multiple exposures. Five worked In various construction trades. Work histories on the cases are limited to employment by the company with two exceptions. Case 1 was a salaried employee at a nearby petrochemical plant from 1948-1964, and Case 6 worked as a pipefitter from 1952-1974 In the same plant. No Information about other potential chemical exposures Is presently available. The detailed examination of v/ork histories in the case-control study offers the best opportunity to establish a connection between a particular chemical exposure or type of work and an excess risk of brain cancer. A detailed literature search for compounds Inducing brain cancer has identi fied 26 different chemicals from experimental animal studies as shown In Table 6. Review of available epidemiological studies provided In Table 7 ucc 048401 -8- DRAFT VI offers several intriguing clues, but little solid documentation for occupa tionally-related brain tumors, except in the case of vinyl chloride. Recent mortality studies of oil refinery workers In Canada ^^and petrochemical workers in Texas ^^suggest the possibility of an excess brain cancer risk among these groups, although as yet no specific causative agent has been identified. i A comparison of experimental studies, epidemiological data, and the plant chemical Inventory shows that vinyl chloride, acrylonitrile, and diethyl sulfate are possible suspect agents for Inducing brain cancer In these workers. On the basis of prior knowledge from human and animal studies, and Its presence In the work environment under poorly controlled circumstances In the past, vinyl chloride must be the first compound considered. However, to date, examination of the work histories of the 19 cases does not support a significant positive association with vinyl chloride exposure, and other agents must be carefully evaluated. The information available indicates that this number of brain tumors Is excessive in a population of this size, and that the tumors are likely to be occupationally-related. There Is no good evidence to Implicate non plant, general environmental factors. A very careful and thorough Investi gation of this situation must be made, since a previously unsuspected chemical exposure may be responsible for this striking appearance of brain cancers In a single petrochemical plant. ucc 048402 REFERENCES Drift VI 1. Fan KJ, Kovl J, Earle KH. The ethnic distribution of primary central nervous system tumors: AF1P, 1958 to 1970. 0 Neuropathol Exp Neurol. 1977; 36: 41-49. 2. Schoenberg BS, Christine BW, Uhisnant JP. The descriptive epidemiology of primary Intracranial neoplasms: the Connecticut experience. Am 0 Epidemiol. 1976; 104: 499-510. 3. Choi NW, Schuman LM, Gullen WH. Epidemiology of primary central nervous system neoplasms. Am J Epidemiol. 1970; 91: 238-259. 4. Mason TJ, McKay FW. U.S. cancer mortality by county, 1950-1969. Bethesda, Md.: National Cancer Institute, 1974. (OHEW publication no. [NIH] 74-615). 5. The Texas Department Of Health and the University of Texas System Cancer Center M.D. Anderson Hospital and Tumor Institute. Impact of cancer on Texas, 1978: 99. 6. U.S. Bureau of the Census. County and city data book, 1972 (A statistical abstract supplement). Washington, D.C.: U.S. Government Printing Office, 1973: 450. 7. Zimmerman HM. Brain tumors: their Incidence and classification In man and their experimental production. Ann NY Acad Scl. 1969; 159: 337-359. 8. Percy AK, Elveback LR, Okazaki H, Kurland LT. Neoplasms of the central nervous system. Neurology. 1972; 22: 40-48. 9. Tabershaw IR, Gaffey WR. Mortality study of workers In the manufacture of vinyl chloride and Its polymers. JOM. 1974; 16: $09-518. 10. Waxweller RJ, Stringer W, Wagoner JK, Jones J. Neoplastic risk among workers exposed to vinyl chloride. Ann NY Acad Scl. 1976; 271: 40-48. 11. Theriault G, Goulet L. A mortality study of oil refinery workers. . JOM. 1979; 21: 367-370. 12. Thomas TL, DeCoufle P, Moure-Eraso R. Mortality among workers employed in petroleum refinino and petrochemical plants. JOM. 1980; 22: 97-103. 13. Vasquez L. Gliomas In a rat fed with 2-acetyl-amlnofluorene. Nature. 1945; 156: 296-297. 14. Maltonl C, Cllibertl A, DiMalo V: Carcinogenicity bioassays on rats of acrylonitrile administered by Inhalation and by Ingestion. Med Lav. 1977; 68: 401-411. ucc 048403 DRAFT VI 15. Druckrey H. Specific carcinogenic and teratoqenic effects of 'indirect' alkylating methyl and ethyl compounds, and their dependency on stages ofontogenic developments. Xenobiotica. 1973; 3: 271-303. 16. Zulch KJ, Mennel HD. Recent results in new models of transplacental carcinogenesis in rats. In: Tomatis L, Mohr U, Davis U, eds. Trans placental carcinogenesis. Lyon: IARC, 1973: 29-44. 17. Takizawa S, Nishlhara H. Induction of tumors in the brain, kidney, and other extra-mammary gland organs by a continuous oral administra tion of N*n1trosobutylurea in Wistar/Furth rats. Gann. 1971; 62: 495-503. 18. Hirono I, Laqueur GL, Spatz M: Tumor induction In Fischer and Osborne-Mendel rats by a single administration of cycasln. JNCI. 1978; 40: 1003-1010. 19. Druckrey H, Kruse H, Preussmann R, Ivankovic S, Landschutz C. Cancerogene alkylierende substanzen III. alkyl-halogenide,-sulfate,sulfonate und ringqespannte heterocyclen. Z Krebsforsch. 1970; 74: 241. 21. Schoental R. Carcinogenic action gf elaiomycin in rats. Nature. 1969; 221: 765-766. 22. Swann PF, Magee PN. Induction of rat kidney tumours by ethyl methanesulphonate and nervous tissue tumours by methyl methane-sulphonate and ethyl methanesulphonate. Nature. 1969; 223: 947-949. 23. Ivankovic S. Experimental prenatal carcinogenesis. In: Tomatis L, Mohr U, Davis W, eds. Transplacental carcinogenesis* Lyon: IARC, 1973: 92-99. 24. Magee PN. Mechanisms of transplacental carcinogenesis by nitroso compounds. In: Tomatis L, Mohr U, Oavis W, eds. Transplacental carcinogenesis. Lyon: IARC, 1973: 143-148. ?5.. Alexandrov VA. [Transplacental blastomogenic action of N-nitroso methylurea on rat offspring]. Vopr Onkol. 1969; 15: 55-61. 26. Napalkov NP. Some general considerations on the problem of transpla cental carcinogenesis. In: Tomatis L, Mohr U, Davis, W, eds. Trans placental carcinogenesis. Lyon: IARC, 1973: 1-13. 27. Ulland B, Finkelstein M, Weisburger EK, Rice OM, Welsburger JH. Carcinogenicity of industrial chemicals propylene imine and propane sultone. Nature. 1971; 230: 460-461. Ucc 048404 DRAFT VI 28. Schoental R, Cavanagh JB. Brain and spinal cord tumors in rats treated with pyrrolizidine alkaloids. JNCI. 1972; 49: 655*671. 29. Maltonl C. Predictive value of carcinogenesis bioassays. Ann NY Acad Scl. 1976; 271: 431*443. 30. Milham S. Cancer mortality patterns associated with exposure to metals. Ann NY Acad Scl. 1976; 271: 243-249. 31. Clemmesen 0. Are anticonvulsants oncogenic? Lancet. 1974; 1: 705*707. 32. Clemmesen J, HJalqrim-Jensen S. On the absence of carcinogenicity to man of phenobarbital. Acta Pathol Microbiol Scand (Suppl). 1977; 261: 38-50. 33. Gold E, Gordls L, Tonascla J, Szklo M. Increased risk of brain tumors in children exposed to barbiturates. JNCI. 1978; 61: 1031-1034. 34. Brooks WH. Geographic clustering of brain tumors In Kentucky. Cancer. 1972; 30: 923-926. 35. Creaoan ET, Fraumenl JF. Deaths from brain tumors In eastern Kentucky 1950-69. JNCI. 1973; 51: 1717-1718. 36. Trouillas P, Menaud G, DeThe G, Almard 6, Dev1c M. Etude epidemiologlque des tumeurs primitives du nevraxe dans la reqlon Rhone-Alpes. Rev Neurol. 1975; 131: 691-708. 37. Cantor KP, Hoover R, Mason TJ, McCabe, LJ. Associations of cancer mortality with halomethanes In drinking water. JNCI. 1978; 61: 979-985. 38. Cooper UC. Cancer mortality patterns In the lead Industry. Ann NY Acad Scl. 1976; 271: 250-259. 39. OeCoufle P. Further analysis of cancer mortality patterns among workers exposed to cutting oil mists. JNCI. 1978; 61: 1025-1030. 40 Mancuso TF, Ciocco A and El-Attar AA. An Epidemiological approach to the rubber Industry. JOM. 1968; 10: 213-232. 41. McMichael AJ, Spirtas R, Kupper LL. An epidemloloqlc study of mortality within a cohort of rubber workers, 19M-72. JOM. 1974; 16: 450-464. 42. Monson RR, Fine, LJ. Cancer mortality and morbidity among rubber workers. JNCI. 1978; 61: 1047-1053. 43. Schuman LM, Choi NW, Gullen WH. Relationship of central nervous system neoplasms to toxoplasma qondll infection. Am J Public Health. 1967; 57: 848-856. UCC e 048405 DRAFT VI 44. Monson RR, Peters OM. Proportional mortality among vinyl chloride workers. Lancet. 1974; 2: 397-398. 45. Byren D, Engholm G, Englund A, Uesterholm P. Mortality and cancer morbidity in a group of Swedish VCM and PVC production workers. Environ Health Perspect. 1976; 17: 167-170. Ucc Q484Q(j Table 1. WORK HISTORY DATA FOR 19 PRIMARY BRAIN CANCER CASES IN A TEXAS PETROCHEMICAL PLANT ucc 048407 Date of Case Hire Date of Death Length of Age at Employment Death (years-months) Job Title Department -1 '2 -3 '4 .5 -6 7 -8 -9 10 -11 -12 -13 14 -15 16 -17 -18 -19 12/16/40 05/18/41 07/29/41 11/30/41 07/09/44 09/18/44 09/18/46 09/26/46 01/12/48 09/21/48 03/02/49 01/25/50 10/19/50 IP/23/50 09/19/51 04/27/53 a0,/17/53 OS/21/53 10/30/53 05/15/64 02/19/66 05/18/76 12/13/65 10/28/79 05/21/74 03/07/79 03/22/73 01/26/71 07/02/75 06/05/71 01/13/68 05/14/74 02/18/80 01/08/74 10/03/56 04/05/62 05/05/71 12/21/78 51 56 66 55 59 55 55 63 53 49 61 66 59 57 52 33 30 44 49 3-6 24-8 31-8 20-4 35-0 0-1 32-3 26-6 1-2 2-1 22-3 16-7 17-1 28-10 22-3 0-1 : 8-7 17-3 24-8 Operator Operator Foreman Operator Boilermaker Operator Laborer/Oller Operator Painter Pipefitter Operator Equip. Operator Operator Operator Machinist Machinist Welghmaster Operator Welghmaster Production Production Maintenance Production Structural Shop Production Maintenance Production Maintenance Maintenance Production Maintenance Energy Systems Production Machine Shop Maintenance Shipping Production Shipping Table 2. CURRENT PLANT WORKFORCE BY COUNTY OF RESIDENCE County of Residence Galveston Harris 8razor1a Other Total Type of Employee Hourly Salaried 1,389 44 41 7 1,481 609 110 15. 4 738 Source: Oata provided by company Total 1,998 154 56 11 2,219 Percent 90.0 6.9 2.5 0.5 100.0 Table 3 DEATH CERTIFICATE DATA FOR 19 PRIMARY BRAIN CANCER CASES IN A TEXAS PETROCHEMICAL PLANT ucc 048409 Race/ Cause of Death Case Sex Residence Place of Birth Death Certificate Medical Records 1 Galveston Texas Carcinoma of Brain Glioblastoma (MR)** 2 Galveston Missouri Malignant Brain Tumor Meningioma (A) 3 W. Harris Texas Brain Tumor Glioblastoma (A) 4 W Galveston Texas 5 W Galveston Louisiana Brain Tumor-Meningioma Meningioma (HR) Glioblastoma Glioblastoma (SP) 6 M'. Galveston Texas Brain Timor-Glial IV No Records Available 7 ffil Galveston Texas Glioblastoma Glioblastoma (MR) 8 tH 6a1veston Texas Glioblastoma Glioblastoma (SP) 9 VM Galveston Massachusetts Cerebellar Timor Metastatic Cerebellar Tumor (SP) 10 111 Harris Texas Astrocytoma Astrocytoma-Grade I (SP) 11 W-! Galveston Texas Malignant Glioma Glioblastoma (MR) 12 IH Galveston New Mexico Glioblastoma Glioblastoma (A) 13 VII Galveston Norway Glioblastoma Glioblastoma (SP) 14+ Uf Galveston Texas Glioma-Grade III Astrocytoma-Grade IV (MR) 15 m Galveston Texas Glioblastoma Glioblastoma (A) 16 VM Karris Texas Glioblastoma No Records Available 17 VK Galveston Louisiana Brain Timor Glioblastoma (A) 18 IJ4 Galveston Texas Malignant Glioma Glioblastoma (SP) 19 WH Galveston Texas Brain Tumor Glioblastoma (A) Data from company records, death certificate not available *Source: HR-Medical Records; A-Autopsy; SP-Surgical Pathology Table 4. BRAIN AND OTHER CNS CANCER MORTALITY, 1950-1969: AVERAGE ANNUAL AGE AOJUSTEO RATES PER 100,000 Location White Male White Female Black Male Black Female United States 4.4 2.9 2.3 1.5 Texas 4.3 2.9 1.9 1.5 Galveston County 4.5 2.9 2.5 2.1 Harris County 4.5 3.6 2.0 1.9 Brazoria County 3.1 3.9 1.2* 1.5 *Based on one case The ranqe of U.S. rates for males for counties with >10 deaths from 1950-1969 were 3.1-5.4 (white) and 1.3-3.9 (black). The range of Texas rates for white males for counties with >deaths from 1950-1969 was 2.3-10.8. Source: U.S. Cancer Mortality by County, 1950-1969, National Cancer Institute, CHEW Pub. No. (NIH) 74-615, Bethesda, Maryland, 1974 ucc 043410 Table 5. RECOGNIZED AND SUSPECT CARCINOGENS IN A TEXAS PETROCHEMICAL PLANT Acrylonitrile Benzene Diethyl sulfate Dloxane Ethylene dichloride Hydrazine Isopropyl Oils Trlchloroethane Trichloroethylene Vinyl chloride Vinylidene chloride ucc 048411 Table 6. EXPERIMENTAL BRAIN CARCINOGENS 2- Acetyl aminofluorene (13) Acrylonitrile (14) l-Ary1-3,3-Dia1kyltriazenes (IS) Azoethane* (16) Azoxyethane* (16) Azoxymethane (15) Butylnitrosourea (17) Cycasin (18) 1,2-Diethylhydrazine (15) Diethylnitrosamine* (15) Diethyl Sulfate* (19) Dimethylbenzanthracene* (20) Dimethyl Sulfate* (19) Elaiomycln (21) Ethyl methanesulphonate (22) Ethylnitrosobluret* (16) Ethylnltrosourea* (23) 1-Methyl-2-Benzyl-Hydrazine* (15) Methyl methanesulphonate (24) Methylnitrosourea* (25) Methylnitrosourethane (intraplacental) (26) Procarbazine* (23) Propane Sultone (27) Propylene Inline (27) Pyrrollzidlne Alkaloids (28) Vinyl Chloride (29) *Transplacenta1 carcinogenesis ucc 048412 Table 7. EPIDEMIOLOGICAL STUDIES: CLUES TO HUMAN BRAIN CANCER ETIOLOGY Aluminum Workers (30) Anti-Convulsant Use (31.32,33) Farm/Rural Residents (3) Geographic Clustering Kentucky (34,35), Rhone Valley (36) Halomethanes in Drinking Water (37) Lead Smelter Workers (38) Machinists (39) Oil Refinery Workers (11) Petrochemical Workers (12) Rubber Workers (40,41,42) Toxoplasmosis (43) Vinyl Chloride Workers (9,10,44,45) ucc 048413 Brain Cancer Cluster Investigation in a Texas City, Texas Chemical Plant Sanford S. Leffingwell, MD, mph Richard Waxweiler, PhD David Glenn, HD John Carvajal, -- Victor Alexander, MD, MSPH October, 1930 UCC 048414 r Introduction: In February of 1979, The National Institute for Occupational Safety and Health (NIOSH) of the Department of Health and Human Services, th Occupational Safety and Health Administration (OSHA), of the Department of Labor, and the Union Carbide Corporation began an investigation of a cluster of brain tumors-at the company's Texas City,,Texas plant. The initial events and the characteristics of the % cases have been described by Dr. Victor Alexander. We here describe the conduct and present status of a case-control study of occupational histories of employees of that plant who developed primary brain tumors. Methods and Materials: The method of case identification has been described by Dr. Alexander; the company was able to identify 12 cases, matching company records with lists of all adult males who were residents of surrounding counties and who died of malignant brain tumors yielded four more cases, three additional cases became ill and died during the course of the study, and three cases have been found so far in the course of determining the vital status of all workers ever employed in the plant. Medical records and tissue specimens were obtained, where possible/ and a best diagnosis was chosen from the available evidence. Ucc 048415 < (9/29/80) page 2 Following the advice of Schoenberg t al., we included all deaths due to primary intracranial neoplasms except those of the pituitary. This excluded one case with a metastatic lesion and one with a congenital anomaly but with no tumor found at autopsy. Two of the most recently discovered cases have not been included, pending confirmation of the diagnosis. Analyses of the residual 18 cases will be done both for the gj;oup as a whole and for the 15 proven gliomas. !<: For each employee* the company completed coding sheets containing identifying personal data* date of each new job title or department code, job code, department accounting code* and date of each layoff or date of termination. Vital status was coded* when known. Every 50th record was copied and sent to NIOSH for independent verification of coding. A random sample of the original records will ^ ',*// * ' be drawn by NIOSH and used for verification of completeness of cohort identification. Six controls were drawn for each case from the pool of all people ever employed at the plant. Cases were matched to potential controls by race and sex; date of birth was matched to within three years; date of first hire .for the control was before that of the case, but not more than three years before; the date the control was last employed was later than the case's last date of employment. The control could be living but, if dead* must not have died of a malignancy. Pools of controls meeting the criteria outlined above were formed and the actual controls used were drawn by random number from the pool. UCC 048416 (3/29/30) page 3 The company provided translations Cor the job and department codes and provided a list of chemicals encountered in each major deoartment - **''''"3 ---- " . <v group. 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 and all codes were 4 transformed to conform to a single coding scheme. Although catalysts have^changed often, there appears to be no problem in characterizing j the feedstocks, intermediate products, and output of each department ) through the years the plant has been in operation. Each jobr department, major department group, or chemical exposure represented by at least three cases was tested for possible 2 significance by X or Fisher's Exact Test. Since this approach is a multiple sampling technique which should lead to about one "significant* association for every twenty jobs, departments, or exposures considered, it is used here as an hypothesis generating mechanism, not as a means of properly testing the hypotheses. For example, since at least one case was exposed to each of nearly 200 chemicals, chance alone should lead to identification of about 10 chemicals whose proportion is significantly different between cases and controls. About half of the ten would be positive and half would be negative associations. (9/29/30) Results: page 4 Only one job code* "Operator" was represented by more than three cases. Table 1 shows the distribution of operators among the cases and controls. There is no significant difference in proportions. * When^analyzed by department accounting code* only the maintenance department* with eight cases* was represented by more than three cases. Table II shows the distribution of maintenance department workers among the cases and controls. Grouping the accounting codes into major departments did not yield any new concentrations of three or more cases. There were no significant differences in proportions. when cases and controls were analyzed by chemical exposures, a new problem was encountered: the exact^exposure^of^a maintenanceman is difficult to characterize accurately* due to their mobility throughout the plant. Accordingly* as a first step, we have examined the data in three ways: in the first* maintenancemen are excluded from analysis: in the second, they are considered to have been exposed to everything in the plant: in the third* they are considered to have been exposed to nothing in the plant. The data are presented in Tables III* IV, and V; only those chemicals to which more than three cases were exposed and which showed a relative risk greater than 1.0 are tabulated. ucc 048418 (9/29/BO) Discussion; page 5 So far in the course of this investigation, no convincing association has been found between any historical exposure and the development of brain tumors at this plant. The incomplete characterization of the maintenance employees' exposures is a significant weakness in the analysis done so far, but fortunately can be corrected, at least in part, by further review of existing records. Some of the maintenance department employees had reasonably well defined exposures; for. example, one case was an instrument repairman whose work rarely took him out of the instrument shop. We plan to define exposures of cases and controls who worked for the maintenance department as completely as possible and study the full data set. At that time, there should also be enough information at hand to study the exposures by latency. It is possible that the tumors seen are the result of a more general effect or exposure* We plan to examine the geographic location within the plant of cases and controls, to see if any pattern emerges, and will atempt to determine the residence at time of first hire, to see if there appears to be any unusual clustering outside the plant* Finally, we must ask whether we are really seeing an effect which requires explanation. The excess of observed over expected reported 2 earlier , combined with an apparent excess when compared to local rates^, could be tbe result of chance. The reported correlations UCC 048419 (9/29/80) page 6 with duration of employment and latency since first employment argue l against this hypothesis but do not refute it. Inquiry into exposures present in other populations with apparent excesses of brain tumors may provide needed additional clue*. * ucc 048420 (9/29/80) P9e 7 Table Zi Distribution of Operators Among Cases and Controls IA. All Cases Operators Cases 9 Controls 49 Non-operators 9 59 Total 18 108 Odds ratio 1.2; X2 * 0.045} p greater than 0.75 Total 58 68 126 IB. Proven Gliomas Operators Non-operators Total Cases 7 8 15 Controls 40 50 90 Odds ratio * 1.1; X2 0.024; p greater than 0.75 Total 47 58 105 ucc 048421 4* * - * (9/29/80) page 8 Tabic 11: Distribution of Maintenance Workers Among Cases and Controls I1A. All Cases Maintenance workers Cases 7 Controls 46 Total 53 Non-maintenance workers 11 62 73 Total 18 108 126 Odds ratio * 0.86i X2 " 0.087) p greater than 0.75 IIB. Proven Gliomas Maintenance workers Non-maintenance workers Total Cases 7 8 15 Controls 37 53 90 Odds ratio 1.3; X2 1.163) p greater than 0.75 Total 44 61 105 * e f \ ucc 048422 i r 19/2S/S0) page 9 Table 111: Distribution Among Cases and Controls of Workers Exposed to Selected fhemipals (Maintenancemen Excluded) IIIA. All Cases Exposed 1. Diethyl ether 2. Ethanol 3. Sodium phosphate salts 4. Lubricating oil 5. Monoethanolamine 6. Ethylene glycol 7. Naphtha 8. Potassium hydroxide Cases 3 3 3 a6 4 3 3 2 Cont. 2 2 2 15 10 8 8 5 Total 5 5 5 21 14 11 11 7 Odds 7.87 3.20 1.73 1.41 1.44 P* 0.07 0.30 0.42 0.80 0.81 Onexposed 1. Diethyl ether 4 21 25 2. Ethanol 4 21 25 3. Sodium phosphate salts 4 21 25 4. Lubricating oil 18 9 5. Monoethanolamine 3 13 16 6. Ethylene glycol 7. Naphtha 4 15 19 4 15 19 8. Potassium hydroxide 5 18 23 Total * Fisher's exact test 7 23 30 \ (9/29/80) page 10 Table III (Con't): Distribution Among Cases and Controls of Workers Exposed to Selected Chemicals (Maintenancemen Excluded) IIIB. Proven Gliomas Exposed 1. Diethyl ether 2. Ethanol 3. Sodium phosphate salts 4. Lubricating oil 5. Monoethanolamine 6. Ethylene glycol , 7. Naphtha 8. Potassium hydroxide Cases 2 2 2 4 r 3 2 2 Cont. 1 1 1 9 6 5 S Total I Odds 3I 3 I 13.0 3I 13 I inf. I 9 I 4.00 7 1.80 7 6.00 0.11 0.23 0.29 0.86 0.98 Unexposed 1. Diethyl ether 2 13 15 2. Ethanol 2 13 15 3. Sodium phosphate salts 2 13 15 4. Lubricating oil 055 5. Monoethanolamine 189 6. Ethylene glycol 7. Naphtha 2 9 11 2 9 11 8. Potassium hydroxide 12 14 Total * Fisher's exact test .14 18 ucc 048424 (9/29/SO) page 11 Table IV; Distribution Among Cases and Controls of Workers Exposed to Selected Chemicals (Maintenancemen Counted as Exposed) ucc 048425