Mortality Study of Workers in 1,3-Butadiene Production Units Identified from a Chemical Workers Cohort Elizabeth M. Ward, John M. Fajen, Avima M. Ruder, Robert A. Rinsky, William E. Halperin, and Cindy A. Fessler-Flesch Division of Surveillance, Hazard Evaluations and Field Studies, National Institute for Occupational Safety and Health, Cincinnati, OH 45226 USA mu I~eelpedbt Hi Urgon UC.rbide: *d, Cati on u s f r h Sie *:production unit within t. hi South Charleston, West Virginia and InStitute, WstM ia. plants ali p t. by-prod- ucts,: and reactants. Departments included n t:d. study were those Wher butadiene .a... primary it b fs por.: et:ln o. ode wras pre.. A^...t..l.... .8. d.eadis werfe lbsevd; tho i "~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~.. .. .x.. .......wf .. .... . za~~~~~~~~~~.pqon. do ...~~~~~~~~~~~~~~~~~~~~..e. .... .... . The .s~tud found a. s.pifan4 leatd. standarded mt.ality rati ( ...... pho sarcoma and' reticulosarcor based on. fouro e cas (SMR 577 95% I ... . . . ~~~~~~~~~~~ ~ ~ ~~~~~~~~~~~~~~~........ ... . . . 157-1480), wich perited: in an alsis. usi mg. county referent rates An...xcess of ly}phosrcoma and o anion. all workers and among workers with routine exposue :io l,3-butadienewa observed in th..ie....on..ly oth*erohorof -u ... .di.n..e * a!!:'.X....S~~~~~~~~... .. .... ..w ,5X ' S; gA~~~~~~~~~~~~~~~~~~~~~~. a... ... ...... ;'w .wo u tono.........r. k.m.ro .. .... o . e. 5; SMR 243; 95% CIi7k that wimost lp renounced. amn woiers or more years (R _ 5; SMR a 657; CI 213-1530)We conclue that the r.esdts .of ths study add to the weigof e s- gestoing that butadiene is" carcinogenic in humansby . Ry won bu an lym- .phosarcoma mortality. reticulosarcoma. . .usw Heylt Pespce 10:598-603>i(1.9.95) .. . ... ... . . ... . . . . . .. . .. .. * ~~~~~~~~~~~~~~~~~~~~~~~~~. . ... ..... . .. :.. 1,3-Butadiene is used in the manufacture of synthetic rubbers (such as styrene-buta- diene rubber or poly-butadiene rubber) and thermoplastic resins (1). Approxi- mately 3000 million pounds of butadiene are produced in the United States each year (2). NIOSH estimates that approxi- mately 9500 workers in the United States are occupationally exposed to 1,3-butadi- ene (1). The International Agency for Research on Cancer (IARC) reviewed the literature on butadiene in 1992 and concluded that there is "limited evidence" of the carcino- genicity of butadiene in humans and "suf- ficient evidence" of the carcinogenicity of butadiene in experimental animals based on three long-term animal bioassays (3). Epidemiologic studies have been conduct- ed among workers exposed to butadiene in the manufacture of styrene-butadiene rub- ber (4-) and among workers involved in the production of butadiene monomer (8-10). Meinhardt et al. (4,5) examined mortality among 2756 white males employed in two styrene-butadiene rubber production facilities in Port Neches, Texas. Elevated, although not statistically significant, increased mortality was observed for lymphatic and hematopoietic neoplasms at one of the two plants [stan- dardized mortality ratio (SMR) = 155], in particular lymphosarcoma and reticulosar- coma (SMR = 181) and leukemia (SMR = 203). These excesses were most pro- nounced among workers hired during World War II. Matanoski et al. (6) ana- lyzed the mortality experience of 13,920 rubber production workers in the United States and Canada and found no signifi- cant increase in mortality from lymphatic or hematopoietic cancer, or any other can- cer site. However, a nonsignificant excess risk of "other lymphatic cancer" (SMR = 202) was noted among production work- ers. An update of this study was reported by Matanoski et al. in 1990 (7). As in the earlier study, there was no significant increase in lymphatic or hematopoietic cancer, or any other cancer site. Produc- tion workers had a significant excess of "other lymphatic cancer" (SMR = 260). A significant excess of all lymphopoietic can- cers was noted for blacks (SMR = 507). A nested case-control study of lymphopoiet- ic cancer was conducted within this cohort. This study examined lymphopoi- etic cancer risk in relation to indices of cumulative butadiene and styrene expo- sure, and found a significant excess risk of leukemia associated with butadiene expo- sure (11). Only one previous study has examined the mortality experience of butadiene pro- duction workers (8-10). This study included 2586 male workers employed at a facility located in Port Neches, Texas, for at least 6 months between 1943 and 1979. Butadiene was produced by the catalytic dehydrogenation of n-butane. The first analysis of the cohort by Downs et al. found eight deaths from lymphosarcoma and reticulosarcoma, yielding a significant SMR of 235 compared to national rates; the SMR was 185 and nonsignificant com- pared to county rates. In the update by Divine et al. (9), there was one additional lymphosarcoma and reticulosarcoma death yielding a significant SMR of 229 (CI = 104-435; county-based SMR's were not reported). In a third update (10), the SMR for lymphosarcoma and reticulosarcoma in the total cohort was not significant (n = 9; SMR = 209; 95% CI = 95-396). How- ever, among the subset of 1056 workers with routine exposure to 1,3-butadiene, there were 6 deaths from lymphosarcoma and reticulosarcoma (SMR = 452; 95% CI = 165-984). To investigate the carcinogenic effects of exposure to butadiene in humans, a cohort of workers employed in butadiene units was identified from within a large cohort (29,139 workers) of chemical workers whose mortality experience has previously been reported (12). Rinsky et al. analyzed the mortality experience of the overall cohort without regard to particular exposures (12). The primary hypothesis of the current study was that exposure to butadiene is associated with excess mortali- ty from malignant neoplasms of the lym- phatic and hematopoietic tissue. A sec- ondary hypothesis was that butadiene would cause excess mortality from neo- plasms of other sites. Background The study population was identified from records of 29,139 workers at three Union Carbide Corporation facilities in the Kanawha Valley, West Virginia: the South Address correspondence to E. M. Ward, NIOSH, 4676 Columbia Parkway, Cincinnati, OH 45226 USA. We thank David A. Dankovic for assistance in interpreting the toxicologic data and Bernice Vehr and the support group of the Industrywide Studies Branch at NIOSH for meticulously coding study information. Received 16 December 1994; accepted 24 February 1995. Environmental Health Perspectives IF; I NO h I I 598 A - -~ 9** .* ee Charleston plant, the Institute plant, and the Technical Center. The first two of these facilities produced butadiene and are included in this study. The South Charleston plant began operations in 1925, around the process of stripping eth- ylene from natural gas. It evolved into a chemical and plastics facility, producing a wide variety of chemical substances, including butadiene, ethylene oxide, poly- ethylene, vinyl chloride resins, and polyols. The Institute plant was originally built by the U.S. government (U.S. Rubber Reserve Corporation) to produce styrene-butadiene rubber to replace the supply of natural rub- ber that was cut off during World War II. This facility was bought by Union Carbide in 1947. The plant was then used as a larg- er production facility for materials devel- oped at the South Charleston plant, such as acetone, isopropanol, butanol, and acetaldehyde. As of 1986, when the Institute plant was sold to Rhone-Poulenc, it had expanded to include the manufac- ture of agricultural chemicals and a wide range of ethylene oxide and propylene oxide-based products. Butadiene production units were iden- tified from a chemical and department index developed by Union Carbide. The index listed all products, by-products, and reactants for each chemical production unit within the South Charleston and Institute plants. Departments were identi- fied where butadiene was a primary prod- uct and neither benzene nor ethylene oxide was present. South Charleston (1941-1965). The butadiene production process at South Charleston involved the recovery of butadi- ene monomer from olefin cracking (see appendix for process description). Among the chemicals used in the process was bis(2- chloroethyl)ether, which also has been eval- uated by IARC for carcinogenicity. The IARC regards bis(2-chloroethyl)ether as having limited evidence of carcinogenicity in animals (13,14), based on a bioassay in which an excess of hepatomas was observed in mice (15). This chemical showed nega- tive results in a bioassay measuring pul- monary tumor response in mice (16) and in a long-term bioassay in rats (17). Rubber Reserve Unit, Institute plant (1943-1946). The U.S. Rubber Reserve Corporation butadiene production unit operated from 1943 to 1946 at the Institute plant. The unit produced butadi- ene monomer indirectly from ethanol (see appendix for process description). As in the South Charleston unit, bis(2-chloro- ethyl)ether was used in this process. In addition, large quantities of acetaldehyde were present. Acetaldehyde is considered by IARC to have "sufficient evidence" of car- cinogenicity in animals (18) based on its ability to induce tumors of the larynx and nasal epithelium in hamsters (19) and rats (20). Institute plant (1959-1971). The Institute plant also produced butadiene monomer as a by-product of olefin crack- ing from 1959 to 1971. The process was the same as described for the butadiene production units at the South Charleston plant; however, in 1965 dimethyl acetamide was substituted for bis(2- chloroethyl)ether. Methods The study population was identified by searching a computer file of work history records of 29,139 workers included in a mortality study of males employed from 1940 to 1979 at any of the Union Carbide chemical plants operating in the Kanawha Valley (12). The computer file of work his- tory records contained a code representing each department in which an individual worked, but not the starting or ending dates. A total of 527 individuals were iden- tified as having ever worked in the depart- ment codes relating to the butadiene units in the South Charleston or Institute plants identified for study. Copies of personnel records were collected for these individuals, and the starting and ending dates of their employment in each department were coded. Only 364 individuals who worked in the departments during the years when butadiene was produced were retained in the study (n = 364). As in the overall Kanawha Valley chemical workers cohort, there was a high proportion of individuals whose race was unknown (28%). Among those whose race was known, 94% were white. Therefore, individuals whose race was unknown were assumed to be white. The Rinsky et al. (12) Kanawha Valley study determined vital status through 31 December 1978. For individuals not known to be deceased as of that date, vital status through 31 December 1990 was determined by matching with records of the National Death Index (NDI). Individuals known to be alive as of 31 December 1978 who were not identified as deceased from National Death Index records 1979-1990 were assumed alive as of 31 December 1990. For workers who were deceased, death certificates were obtained from state vital statistics offices and were coded according to the International Classification of Diseases (ICD) revision in effect at the time of death. The mortality experience of the cohort was compared to United States and to Kanawha County mortality rates using a modified life-table analysis system (LTAS) developed by NIOSH (21,22). The county rate analysis was restricted to the time peri- od 1960 through 1990 for which county referent rates are available in the NIOSH lifetable. Standardized mortality ratios, 95% confidence intervals, and two-sided p- values were calculated. Confidence inter- vals and p-values were calculated using an exact method (if either the observed or expected was less than 6) or an approxi- mate method (if observed or expected fre- quencies were 6 or more). Because of the small size of the cohort and therefore the small numbers of deaths, latency and dura- tion analyses were performed by simply dichotomizing both latency and duration categories so that approximately equal numbers of expected deaths were below and above the cutpoints. For specific cancer site categories in which a statistically significant elevated SMR was observed, concomitant chemical exposures of the deceased workers were identified. This was accomplished by list- ing all departments other than butadiene in which their personnel records indicated they worked and then identifying the chemicals used and produced in each department from the index assembled by Union Carbide. Results Among the 364 persons who were identi- fied as working in any of the butadiene production units, 277 individuals worked in the Rubber Reserve Unit which pro- duced butadiene from ethanol, and 87 worked in the units at the South Charleston and Institute plants which pro- duced butadiene from olefin cracking. Among these 364 persons, 176 (48.3%) were alive, 185(50.8%) were deceased, and 3 (0.8%) had unknown vital status as of the study end date of 31 December 1990. Table 1 shows the mortality pattern of the total cohort through 1 January 1990 based on U.S. referent rates. As in the previous study of the mortality experience of 29,139 workers in the three Kanawha Valley plants through 1978 (3), the SMR for deaths from all causes in the butadiene production cohort was <1.00. The SMR for deaths from all malignant neoplasms was 1.05 (CI = 0.78-1.40), which was higher than the SMR for deaths from all malignant neoplasms in the larger chemical workers cohort (SMR = 0.93; CI = 0.88-0.99) (12). Among the 92 specific causes of death and 26 major categories examined in the NIOSH lifetable, there was only one significantly elevated SMR, which was for the category "lymphosarco- ma and reticulosarcoma" (n = 4; SMR = 5.77; CI = 1.57-14.8). County-based analyses, which covered only the time peri- od 1960-1990, resulted in a similar SMR (SMR = 5.78; CI = 1.57-14.8). Table 2 provides the SMRs for lym- phosarcoma and reticulosarcoma by dura- Volume 103, Number 6, June 1995 599 4.,'. -I- Table 1. Mortality (through 31 December 1990) from specific causes for butadiene production workers Cause Observed Expected SMR 95% Cl Tuberculosis 0 1.72 Malignant neoplasms Buccal and pharynx 1 1.29 0.77 0.02-4.29 Digestive organs 11 12.2 0.90 0.45-1.61 Stomach 5 2.06 2.41 0.79-5.68 Respiratory system 19 16.6 1.14 0.69-1.79 Trachea, bronchus, and lung 19 15.8 1.20 0.72-1.88 Male genital organs 3 3.70 0.81 0.17-2.37 Urinary organs 1 2.32 0.43 0.01-2.39 Lymphatic and hematopoietic 7 3.99 1.75 0.70-3.61 Lymphosarcoma and reticulosarcoma 4 0.69 5.77 1.57-14.8 Hodgkin's disease 0 0.34 Leukemia and leukemia 2 1.62 1.23 0.15-4.44 Other lymphatic or hematopoietic 1 1.33 0.75 0.02-4.17 Other sites 6 5.36 1.12 0.41-2.44 Neoplasms of benign and 0 0.62 unspecified nature Diabetes melitis 2 2.90 0.69 0.08-2.49 Blood and blood-forming diseases 0 0.54 Alcoholism and mental disorders 0 1.21 - Nervous system diseases 1 2.14 0.47 0.01-2.59 Diseases of the heart 75 82.2 0.91 0.72-1.14 Diseases of the circulatory system 21 18.2 1.15 0.71-1.76 Respiratory system diseases 7 13.9 0.50 0.20-1.03 Digestive system diseases 5 9.36 0.53 0.17-1.25 Diseases of genitourinary system 2 2.96 0.68 0.08-2.44 Diseases of the skin and 0 0.17 subcutaneous tissue Musculoskeletal diseases 0 0.35 Symptoms and ill-defined conditions 2 2.48 0.81 0.09-2.91 Accidents 10 10.3 0.97 0.46-1.78 Suicide and homicide 3 4.62 0.65 0.13-1.90 All other causes 3 2.88 1.04 0.21-3.04 Certificates not obtained 6 All cancers 48 45.5 1.05 0.78-1.40 All causes 185 202.2 0.91 0.79-1.06 SMR, standarized mortality ratio. Table 2. Standardized mortality ratios (SMRs) for lymphosarcoma and reticulosarcoma by duration of employment and time since first employment in butadiene production processes Duration of employmentsb < 2 years 2 2 years Total Latencya Observed SMR Observed SMR Observed SMR < 30 years 1 4.92 0 1 2.41 2 30 years 0 3 19.8** 3 10.8** Total 1 3.03 3 8.27* 4 5.77* aLatency categories were selected to divide expected deaths from all causes into two approximately equal categories. There were 95 expected deaths in the < 30 years latency category and 107 in the 2 30 rears latency category. Duration of employment categories were selected to divide expected deaths from all causes into two approximately equal categories. There were 100 expected deaths in the < 2 years duration category and 102 in the ? 2 years duration category. *p < 0.05; **p < 0.01. tion of employment in butadiene produc- tion processes and latency (defined as time since first employment in butadiene pro- duction processes). Three of the four deaths from lymphosarcoma and reticu- losarcoma occurred in the >2 years' dura- tion and >30 years' latency categories (SMR = 19.8; CI = 4.08-57.8). Table 3 provides additional information about the work histories of the four individuals, three of whom worked in the Rubber Reserve unit at the Institute plant. Aside from their assignments to butadiene production units, there were no commonalities among the four cases except that two had been assigned to an acetaldehyde unit, one for 8 years and one for 29 years. There was a statistically nonsignificant excess of stomach cancer in the overall cohort (n = 5; SMR = 2.43; CI = 0.79-5.68) that was most pronounced among workers employed in the Rubber Reserve plant for over 2 years (n = 5; SMR = 6.57; CI = 2.13-15.3; Table 4). County-based analyses for the overall cohort showed identical SMRs of 2.93 for the county and U.S. refer- ent rates 1960-1990. Table 5 provides information about the work histories of the five individuals who died of stomach can- cer. Aside from their assignments to the butadiene unit, the only commonality among the work histories of the cases was that two had been assigned to "mainte- nance of grounds." Discussion The major finding of this study is excess mortality from lymphosarcoma and reticu- losarcoma among workers employed in butadiene production processes located within two large chemical plants. An excess of lymphosarcoma and reticulosar- coma (SMR = 239) was observed in the only other butadiene production cohort previously studied (8-JO). The latter plant used a different process (the catalytic and oxidative dehydrogenation of n-butane) from either of the two processes used by Union Carbide. A nonsignificant excess in lymphosarcoma and reticulosarcoma deaths was also found at one of two plants producing styrene-butadiene rubber (4). Elevated lymphoma incidence has also been observed in mouse bioassays (23-26). A prior mortality study of workers at the Union Carbide's Kanawha Valley plants found a significant excess of lym- phosarcoma and reticulosarcoma (SMR = 1.40; CI = 104-187) (12). An excess of deaths from this cause in the county where the plant is located (Kanawha County, West Virginia) has been noted previously (27. The county rate analyses in the cur- rent paper show that the expected number of deaths for lymphosarcoma and reticu- losarcoma are approximately 15% higher in Kanawha County than in the U.S. pop- ulation. Thus, geographical variation does not explain a substantial proportion of the increased risk among workers in butadiene units. A previous study which evaluated occupational risk factors for lymphopoietic cancers within Union Carbide's Kanawha Valley plants did not specifically evaluate the risks for lymphosarcoma and reticu- losarcoma, but instead included these tumors in the broader grouping, "non- Hodgkin's lymphoma" (28). That study did not find an association between buta- diene exposure and non-Hodgkin's lym- phoma. Those results cannot be directly compared to findings of the current study because the periods of case ascertainment, disease groupings, and classification of butadiene exposure were different. Our study also found an excess of stom- ach cancer among workers employed in the Rubber Reserve Unit for over 2 years. Review of the work histories of all the indi- viduals who died of stomach cancer did not reveal any likely confounding exposures. Stomach cancer was in deficit in the overall Kanawha Valley chemical worker cohort followed through 1978 (SMR = 79; CI = Environmental Health Perspectives 600 A , Mas-2 e AIIg p*e-ar-cc. Table 3. Work histories of individuals who died of lymphosarcoma and reticulosarcoma Approximate length Beginning year of employment Time from Butadiene Age at death of employment in butadiene initial exposure Year department Other departments/ (years) in butadiene unit (months) to death (years) of death worked in exposures 65 1942 39 33 1975 Rubber reserve Acetaldehyde unit,a outside work 64 1943 35 36 1979 Rubber reserve Maintenance of grounds, acetaldeh de unitaupper island chemicals 52 1946 9 25 1971 Rubber reserve Isopropanol-acetone,C laborer, maintenance, general stores and purchasing 63 1952 96 32 1984 Olefin unit, Maintenance labor, gas plants/ S. Charleston olefins,d outside work, acetylene unit,C weighmaster, chemicals and resins-packaging and shipping aAcetaldehyde unit: A variety of chemicals, many requiring acetaldehyde as a reaction material, were produced in this department. These included vinyl isobutyl ether, vinyl ethyl ether, vinyl butyl ether, vinyl methyl ether, hexaldehyde, 2-ethyl butyraldehyde, propionaldehyde, 2-methyl pentaldehyde, methyl isoamyl ketone, 2,3-dimethyl pentaldehyde, ethyl propenal ether, ethyl acetate, and 2-methyl pentaldehyde. Refined acetaldehyde was also produced. bUpper island chemicals area units: A large variety of chemicals, including ethers, ketones, alcohols, and acids were produced in these units. Clsopropanol-acetone department: Materials handled in this department included propylene, diisopropanol sulfate, fuel gas, water, sulfuric acid, and "merrill oil." Products included isopropanol, diisopropyl ether, isopropyl oils, and weak sulfuric acid. dGas plants/olefins: Materials handled in this department included butane, propane, acetone, gasoline, butadiene vent gas, methanol, blowbacks from ethylene absorbers at "MB," polyethylene, chlorohydrin, propylene absorbers from isopropanol, caustic 20%, anti-oxidant, "DuPont No. 5," wood chips, and alumina pel- lets. Products included ethylene, propylene, and acetylene. By-products included crude butadiene, propane, "pyrofax," benzene, hydrogen-methane, sulfur sat- urated wood chips, hydrogen, and residues. eAcetylene unit: Process materials included calcium carbide, sodium hydroxide, and sulfuric acid. Products included acetylene and calcium hydroxide. 59-104) (12). Prior epidemiologic studies of butadiene-exposed workers have report- ed a decreased SMR for digestive cancers overall (4), a decreased SMR for stomach cancer (8-J1) and a slightly elevated SMR (1.05) for stomach cancer which was higher among black workers (SMR = 1.45) and maintenance workers (SMR = 1.51) (7). Carcinomas of the forestomach have been found to be elevated in two mouse bioas- says of 1,3-butadiene (23-26). The current study has several limita- tions. One limitation is that cancer mortal- ity, rather than incidence, was considered, and thus any increased risk at cancer sites with high survival rates might not be detected. This limitation could not be readily overcome because there is no popu- lation-based cancer registry in the Kanawha Valley area. It is not known whether there are living individuals in the cohort who have been diagnosed with lym- phosarcoma or reticulosarcoma. An impor- tant limitation is the potential for con- founding exposure both within the butadi- ene production units and outside the units. We attempted to address the issue of con- founding in the design of the study by selecting a priori only departments where butadiene was a primary product and ben- zene and ethylene oxide were not present. We also identified potential confounding exposures outside the butadiene units by examining the work histories of cases to determine whether there were common exposures. Among the potential confound- ing exposures which could not be con- trolled for in the study design, acetalde- hyde was of the greatest concern both Table 4. Standardized mortality ratios (SMRs) for malignant neoplasms of the stomach by duration of employment and time since first employment in the rubber reserve plant Duration of employmentb < 2 years 2 2 years Total Latencya Observed SMR Observed SMR Observed SMR < 30 years 0 2 5.63 2 2.25 2 30 years 0 - 3 7.40 3 3.69 Total 0 5 6.57* 5 2.94* aLatency categories were selected to divide expected deaths from all causes into two approximately equal categories. There were 73 expected deaths in the < 30 years latency category and 91 in the 2 30 rears latency category. Duration of employment categories were selected to divide expected deaths from all causes into two approximately equal categories. There were 87 expected deaths in the < 2 years duration category and 77 in the ? 2 years duration category. *p < 0.01. because it was present in the rubber reserve process and because two of the four indi- viduals who died of lymphosarcoma and reticulosarcoma worked in the acetalde- hyde unit. In addition, a case-control study of risk factors for lymphopoietic can- cer within Union Carbide's Kanawha Valley chemical plant (28) found an elevat- ed odds ratio for non-Hodgkin's lym- phoma associated with exposure to acetaldehyde, but noted that odds ratios and duration trends were similar for acetaldehyde and acrylonitrile because of concomitant use of the two chemicals. To examine further whether the risk of lymphosarcoma and reticulosarcoma might be attributable to an elevated risk associat- ed with the acetaldehyde unit, to which two of the four cases had been assigned, we identified 233 workers from the large cohort of 29,139 who had ever been assigned to this unit and followed their mortality through 1991. A total of 48 deaths were identified. Aside from the two deaths from lymphosarcoma and reticu- losarcoma previously identified among workers who had been included in the butadiene production study, there were no other deaths from this cause. The toxicologic data are consistent with the conclusion that the excess of lym- phosarcoma and reticulosarcoma found in the study are likely to be related to butadi- ene rather than confounding exposure to acetaldehyde. Acetaldehyde has only been demonstrated to induce upper respiratory tumors in rodents at levels (1000 ppm and above) substantially above the levels at which acetaldehyde has been demonstrated to cause eye irritation in humans (29). In contrast, butadiene has been shown to cause an increase in incidence of lympho- cytic lymphomas and histiocytic sarcomas in mice (formerly known as type A reticu- lum cell sarcomas) at concentrations as low as 200 ppm, with marginally signifi- Volume 103, Number 6, June 1995 601 A - , Table 5. Work histories of individuals who died of stomach cancer Beginning year Approximate length Time from Butadiene Age at death of employment in of employment initial exposure Year department (years) butadiene unit in butadiene (months) to death (years) of death worked in Other departments/exposures 75 1943 37 21 1964 Rubber reserve None 67 1944 30 18 1962 Rubber reserve None 65 1943 42 33 1976 Rubber reserve Maintenance of grounds, polyethylene department 65 1943 54 33 1976 Rubber reserve Gas plants/olefinsb and S. Charleston 74 1943 29 32 1975 Rubber Reserve Maintenance of grounds, janitors and watchmen, general maintenance, building services, and guards a"Dowtherm," "Ucon," "Heat transfer fluid 500," butyl hydroxy toluene, "Super floss" and "Vazo." Products were various grades of homopolymers and copoly- mers, recovered vinyl acetate, unreacted ethylenes, and oils. bGas plants/olefins: Materials handled in this department included butane, propane, acetone, gasoline, butadiene vent gas, methanol, blowbacks from ethylene absorbers at "MB," polyethylene, chlorohydrin, propylene absorbers from isopropanol, caustic 20%, anti-oxidant, "DuPont No. 5," wood chips, and alumina pel- lets. Products included ethylene, propylene, and acetylene. By-products included crude butadiene, propane, "pyrofax," benzene, hydrogen methane, sulfur satu- rated wood chips, hydrogen, and residues. cant increases in histiocytic sarcomas down to 20 ppm (24,25). When studying workers employed at large chemical production complexes, it is impossible to rule out the potential impor- tance of confounding exposures. Ott et al. (28) noted that the average production worker at these plants was exposed to 58 different chemicals, many of which were correlated. Other studies conducted in the same chemical worker population have identified associations of lymphosarcoma and reticulosarcoma with maintenance (Teta J, unpublished data) and strong acid ethanol production (30), and the broader category non-Hodgkin's lymphoma with units using acetaldehyde (28). These obser- vations were made in efforts to investigate the observed excess of death for the original cohort study of 29,139 workers or in sur- veillance studies. The current study, on the other hand, was initiated in 1986 to exam- ine the hypothesis that exposure to butadi- ene might be related to hematopoietic can- cer. If exposure data were available, the association between mortality from lym- phosarcoma and reticulosarcoma might be evaluated by determining whether there is evidence for an exposure-response relation- ship. However, there are no air monitoring data for any of the butadiene production processes, and thus air concentrations of butadiene (and other chemicals) cannot be estimated. Personnel records do not indi- cate the types of tasks or job assignments an individual worker had; thus, there is no way to know whether the four individuals who developed lymphosarcoma or reticu- losarcoma were exposed to higher concen- trations of butadiene than other members of the cohort. Finally, the U.S. Rubber Reserve plant operated for only 4 years, and thus we could not evaluate the effects of prolonged exposure to this process. Despite the limitations outlined above, the study has demonstrated an excess of mortality from lymphosarcoma and reticu- losarcoma, which is consistent with the only other butadiene production cohort previ- ously studied. Finding an excess of neo- plasms of the lymphatic system in relation to butadiene exposure is consistent with the mouse bioassay data as well (18,19). We conclude that the results of this study add to the weight of the evidence suggesting that butadiene is carcinogenic in humans. Appendix. Process Description Rubber Reserve Process: Production of Butadiene from Ethanol (Institute Plant, Early 1940s) The rubber reserve plant was operated by the Union Carbide Corporation during World War II under contract with the U.S. government. The rubber reserve process produced butadiene indirectly from ethanol. To better understand the process, the plant may be considered as being composed of four major divisions: 1) an acetaldehyde conversion system, 2) a butadiene conver- sion system, 3) a butadiene purification sys- tem, and 4) a recovery distillation system. In the acetaldehyde conversion system, the ethanol was introduced into a catalytic converter containing a copper-chromium catalyst and was partially converted to acetaldehyde. The converters were heated by circulating liquid Dowtherm. The reac- tion involved was Ethanol -> Acetaldehyde + Hydrogen Cu - Cr In this step, side reactions occurred that resulted in the formation of acetic acid, ethyl acetate, butylaldehyde, and butanol. The equipment in the butadiene con- verter system is similar to that used in the acetaldehyde conversion system. The process was as follows: Ethanol + Acetaldehyde -* Butadiene + Water Titanium Oxide In passing through the titanium oxide, the combined ethanol and acetaldehyde are 15-20% converted to butadiene at an effi- ciency of 60-65%. Conversion of this mix- ture resulted in the formation of a large number of by-products. Among these were ethylene, ethane, propylene, propane, butylene, butane, carbon dioxide, carbon monoxide, diethyl ether, butyraldehyde, ethyl acetate, methyl ethyl ketone, carbon, acetic acid, butanol, and other unidentified hydrocarbons. The major process steps in the purifica- tion phase were as follows: 1) stripping the crude butadiene from the condensed liq- uids of the butadiene converters, 2) removal of acetaldehyde from the butadi- ene, and 3) removal of butane and buty- lene from the butadiene. The crude butadiene was removed from the condensate collected from the catalytic converter by distillation in a heat- ed column. The crude butadiene at this point is a mixture of butenes, butane, and the binary azeotrope of butadiene and acetaldehyde. The crude mixture, includ- ing the azeotrope with acetaldehyde, was passed through a water scrubber to absorb the acetaldehyde present in the vapor. The acetaldehyde-free vapor from the scrubber was then fed to another column and the butadiene was absorbed by Chlorex (di-2- chloroethyl ether). The Chlorex preferen- tially absorbed the butadiene and allowed the butylenes and butane to pass out of the column. The remaining vapors consisted largely of butadiene, water, and some Chlorex. Chlorex, when heated, breaks down and forms dilute hydrochloric acid. Caustic soda was used in the solvent sys- tem to neutralize the hydrochloric acid. The final step in the purification process required the water and the Chlorex to be condensed and separated. The resulting product is butadiene at a purity of 99.5%. The function of the recovery distilla- tion system was to reconcentrate the unre- Environmental Health Perspectives 602 ESE M* *** acted acetaldehyde and ethanol from the conversion system, remove the by-products from the material cycle and to feed the converters. Union Carbide Process: Recovery of Butadiene from Olefin Cracking (Institute Plant, 1959-1971 and South Charleston Plant, 1941-1965) The Union Carbide olefin unit used a high-temperature cracking process to pro- duce ethylene from hydrocarbons. The process was developed to recover butadiene as a by-product of the normal ethylene process. The relatively pure mixture of the four carbon molecules (less than 50% butadiene) was supplied from three sources in 1 0,000-gallon capacity feed tanks. Crude feed from the feed tanks was fed to an absorber column, and Chlorex was the solvent used to desorb the butadiene. The Chlorex, after absorption of the major- ity of the butadiene, was routed to a strip- ping column. The crude butadiene at this phase of the process was 88-90% pure. The material was then scrubbed with water to remove any aldehydes which might have been present. The condensed, partially refined butadiene was then compressed and piped to the 10,000-gallon capacity inter- mediate storage tanks prior to recracking. To control the formation of popcorn-type polymers, sodium nitrite was added to the process stream to remove the oxygen. Final refining of butadiene was a distil- lation process carried out in a two-column system. 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