Document 106bnE6Ln38O575N7ByZXJG7j

[CANCER RESEARCH SO. 6S92-4J99. October IS. 1990] Carcinogenicity of 1,3-Butadiene in C57BL/6 x C3H Fj Mice at Low Exposure Concentrations [L 0 J000 Ronald L. Melnick,1 James Huff, Billy J. Chou, and Rodney A. Miller \ational Institute of Environmental Health Sciences, Research Triangle Park, Sorth Carolina 27709 fR. L \f,, J. H.J, and Battelle Pacific Northwest Richland. Washington 99SS2 /B. J. C., R. A. M.J ABSTRACT The carcinogenicity of inhaled 1,3-butadiene was evaluated in C57BL/ 6 x C3H F, mice exposed lo concentrations of this gas ranging from 6.25 to 625 ppm. Butadiene is a high production volume chemical, used mainly in the manufacture of synthetic rubber. In these 2-yr inhalation studies, a potent multisite carcinogenic response was observed, including neo plasms of the lung at concentrations as low as 6.25 ppm. Early occurrence and extensive development of lethal lymphocytic lymphomas in mice exposed to 625 ppm of butadiene reduced the number of animals at risk for the expression of later developing neoplasms at other sites: at lower exposure concentrations, dose responses were demonstrated for hemangiosarcomas of the heart and neoplasms of the lung, forestomach, Harderian gland, preputial gland, liver, mammary gland, and ovary. So far, no long-term studies on butadiene have been conducted at exposure concentrations that have not shown a carcinogenic response. In separate experiments with reduced exposure durations, butadiene induced neo plastic responses at multiple organ sites even after only 13 wk of exposure. Because of the correspondence between these animal data and recent epidemiology findings, there is a worldwide public health need to reevaluate current workplace exposure standards for 13-butadiene. INTRODUCTION tude of response was demonstrated in these carcinogenicity studies of butadiene (11, 12). The results of those studies prompted the American Conference of Governmental Indus trial Hygienists to lower their recommended threshold limit value for butadiene in the work environment from 1000 ppm to 10 ppm (13). Meanwhile, the Occupational Safety and Health Administration has determined that there are significant pre dicted risks associated with occupational exposure to 100 ppm of butadiene over a working lifetime (14). Most importantly, recent epidemiological findings from the rubber industry indi cate an association between occupational exposure to 1,3-butadiene and the development of lymphatic and hematopoietic cancers (15, 16). This paper reports our 2-yr inhalation studies of butadiene in mice exposed to concentrations ranging from 6.25 to 625 ppm and separate studies using variable exposures and dura tions. Dose-response relationships are reported for the various neoplastic lesions induced by butadiene, and the relationship between exposure concentrations and durations of exposure on the outcome of butadiene-induced carcinogenicity has been assessed. 1,3-Butadiene, a colorless gas (bp, -4,4*C) generally pro duced as a coproduct of ethylene production, is used mainly in MATERIALS AND METHODS the manufacture of synthetic rubber (styrene-butadiene rubber or polybutadiene rubber) and of thermoplastic resins (I). The annual production volume of butadiene is approximately 12 billion pounds worldwide and 3 billion pounds in the United States (2). The United States Environmental Protection Agency Chemicals. Liquified 1.3-butadiene of 99*% purity, containing trace amounts of r-butyl catechol, a peroxide inhibitor, was obtained from Phillips Chemical Co. (Bomer, TX). Concentrations of the dimer, 4vinyl-1-cyclohexene, in the cylinder headspace were determined by gas chromatographic analysis. Cylinders were not retained for use if the estimates that between 5300 and 8200 workers are exposed to dimer content was greater than 150 ppm. Butadiene gas was metered butadiene in facilities which produce the monomer or which process the monomer into polymers (3). Occupational exposure to butadiene is generally less than 20 ppm: however, in a recent industrial hygiene survey, it was found that exposures in certain jobs were as high as 375 ppm (4). Butadiene has also been identified in automobile exhaust and cigarette smoke (5). Butadiene is mutagenic to Saimonello typhimurium (strains TA1530 and TA1535) in the presence of S9 metabolic activa tion systems (6). The mutagenicity of butadiene may be due to to Hazelton 2000 chambers (Harford Division of Lab Products. Inc., Aberdeen. MD) via a distribution system and diluted in the fresh air chamber inlets. Chamber concentrations of 1,3-butadiene were moni tored continuously during the exposure periods utilizing a HewlettPackard 5840 gas chromatograph equipped with a flame ionization detector (oven temperature, 120'C; gas chromatography column. 12- x '/-in nickel column packed with 1% SP-1000 on 60/80 Carbopack B (Supelco. Inc.. Bellefonte. PA): carrier gas, nitrogen (20 ml/min)j. The daily mean concentrations of 1,3-butadiene, distributed uniformly in the chambers, were within 2% of the target concentrations. its oxidative intermediates, butadiene monoxide and diepoxy Animals. Five-wk-old male and female C57BL/6 x C3H F. (hereafter butane (7), which are direct acting mutagens in Salmonella (8, 9). Butadiene was also genotoxic to bone marrow cells of exposed mice, causing an increase in the frequency of chromo somal aberrations, sister chromatid exchanges, and micronucleated erythrocytes (10). At exposure concentrations nearly equal to and one-half the Occupational Safety and Health Administration 8-h timeweighted average workroom exposure standard of 1000 ppm, called B6C3Fi) mice, obtained from the Frederick Cancer Research facility (hrederick, MD), were quarantined and acclimatized for 10 days prior to the start of the study. Stainless steet Hazelton 2000 chambers were used, and animals were exposed in individual wire mesh cage units, each having a floor area of 106 cm1. The chamber environ ment was maintained at 24 2'C and 55 15% relative humidity with a chamber air flow of 15 air changes/h. Fresh softened tap water and NIH-07 diet were available ad libitum, except when the feed was removed during the exposure periods and overnight prior to the 40- butadiene was carcinogenic in mice (I l) and rats (12). A species and 65-wk necropsies. difference with respect to sites of tumor induction and magni-* 1 Exposure Regimen. Groups of 70 to 90 male and female B6C3Ft Received 7/26/89; accepted 7/13/90. The costs of publication of this article were defrayed in pan by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 To whom requests for reprints should be addressed. mice were exposed to 0. 6.25. 20, 62.5, 200, or 625 ppm of butadiene, 6 h/day. 5 days^wk for up to 2 yr. As many as 10 animals/group were killed and evaluated after 40 and 65 wk of exposure. Additional studies, in which exposure to butadiene was stopped after limited exposure periods, were included to assess the relationship between exposure level 6592 UJ, Or * VRD 0002037124 CARCINOGENICITY OF I.J-BL'TAOIENE and duration of exposure on the outcome of butadiene-induced carcin ogenicity. In the stop-exposure studies, groups of 50 male mice were exposed to one of the following regimens: (a) 625 ppm for 13 wk; (6) 200 ppm for 40 wlc: (c) 625 ppm for 26 wk; or (rf) 31^ppm for 52 wk. After the exposures were terminated, these groups &f animals were placed ip control chambers for the remainder of the 104-wk studies. The total exposure to butadiene (concentration x duration of exposure) was approximately equivalent for Groups a and b and provided about half (he total exposure given to Groups c and d. Histopathology. All animals that died during the study or that were killed at the end of the exposure period received a complete gross necropsy and histopathologtcal examination, All moribund animals and those remaining at the end of the study wefe killed by carbon dioxide asph>xiation and necropsied immediately. Tissue samples, preserved in 10% neutral buffered formalin, were embedded in paraffin, sectioned, and stained with hematoxylin and eosin. The following tissues were examined microscopically: gross lesions and tissue masses; bronchial, mediastinal, mandibular, and mesenteric lymph nodes; sali vary gland: sternebrae (including marrow); thyroid: parathyroid: small intestine: large intestine; liver; gall bladder prostate: testes, epididymis, and seminal vesicles: ovaries; lungs and mainstem bronchi; nasal cavity and turbinates; heart: esophagus; stomach: uterus: brain: thymus; lar ynx; trachea; pancreas; spleen; kidneys; adrenals: urinary bladder pi tuitary': and mammary gland. Statistical Analyses. Differences in survival were analyzed by life table methods (17), and incidences of neoplastic lesions (the ratio of the number of animals bearing such lesions at a specific anatomical site to the number of animals in which that site was examined) including information on time of death were analyzed by life table tests, logistic regression analyses. Fisher exact analyses, and Cochran-Armitage trend analyses (18, 19). Tumor rates were adjusted for intercurrent mortality using the survival-adjusted quantal response test described by Portier and Bailer (20), with a power value equal to 3 (21). female group was observed with this endothelial cell tumor. These neoplasms are particularly important because heman giosarcomas of the heart are uncommon in untreated male or female B6C3F) mice, occurring at a rate of about 0.04%, or one of every 2500 mice. Interestingly, the incidence of heman giosarcomas of the heart was greater in male mice exposed to 200 ppm than in those exposed to 625 ppm. Vet, it is evident from Fig. 1 (where the cumulative incidence of lymphocytic lymphoma or hemangiosarcoma of the heart is plotted against the number of weeks on study) that, for male mice exposed to 200 or 625 ppm of butadiene, the early and extensive develop ment of lethal lymphocytic lymphomas at 625 ppm resulted in a reduced number of mice at risk in that exposure group for the later developing hemangiosarcomas. The impact of early mor tality on the expression of late developing tumors is largely accounted for in the mortality-adjusted tumor rates shown in Tables 1 and 2. Furthermore, when the rates of hemangiosar coma of the heart in early death animals were compared over 25-wk intervals for male mice exposed to 200 or 625 ppm of butadiene, it was found that the rates of this neoplastic lesion during these time intervals were nearly equivalent at these two exposure concentrations for the first 75 wk of the study. After that time, a high rate of hemangiosarcoma of the heart (50%) was observed in the 200-ppm exposure group: there were no surviving animals in the 625-ppm exposure group. Thus, for male mice exposed to concentrations of butadiene below 625 ppm, the dose response for butadiene-induced hemangiosarco mas of the heart is more clearly demonstrated. Mortalityadjusted dose-response curves for lymphocytic lymphoma, he mangiosarcoma of the heart, and neoplasms of the lung, fore stomach, and Harderian gland in male mice are shown in Fig. RESULTS Survival was reduced for male and female mice exposed to 20 ppm of butadiene or higher concentrations, largely due to the development of compound-related malignant tumors (Ta bles 1 and 2). All of the mice exposed to 625 ppm died by Wk 65. The percentage of animals bearing malignant tumors in creased from about 30% in the control groups to nearly 90% in the 625-ppm exposure groups. However, the best approach for detecting potential carcinogenic effects of chemicals is to com pare specific tumor incidences between dosed and control groups rather than comparing the overall proportion of animals with malignant tumors. Lymphocytic lymphomas, of thymic origin, appeared as early as Wk 23 and were the major cause of death for male or female mice exposed to 625 ppm; the incidence of these neoplasms was greater in males than in females (Tables 1 and 2). Malignant lymphomas were classified according to the criteria of Frith and Wiley (22). Most butadiene-induced lymphomas were well differentiated and lymphocytic, and they appeared to originate in the thymus. Furthermore, the thymus was the most fre quently and prominently affected organ. The incidence of lym phocytic lymphomas was also increased in females exposed to 200 ppm, but not at lower concentrations. After Wk 65, malig nant lymphomas had less thymic involvement, and the other histological types (histocytic and mixed-cell lymphomas) more commonly associated with the spontaneous lymphoma of B6C3F, mice were observed in all remaining groups. The incidence of hemangiosarcomas of the heart was in creased in male mice exposed to 62.5. 200, or 625 ppm. and in female mice exposed to 200 or 625 ppm. In addition, one animal from both the 20-ppm male group and the 62.5-ppm 2. The impact of an early occurring lethal tumor on the detec tion of later developing neoplasms at other sites is further demonstrated by the finding that, in 15 male mice in the 625ppm exposure group which did not die early with lymphocytic lymphoma (17% of the animals), the occurrences of heman giosarcomas of the heart (five), alveolar-bronchiolar neoplasms (six), forestomach neoplasms (eight), and Harderian gland neo plasms (six) accounted for 66% of the total occurrences of these neoplasms in that exposure group. The incidence of alveolar-bronchiolar neoplasms of the lung in male mice was increased at 62.5 ppm and higher concentra tions compared with controls. Statistical significance at 625 ppm was obtained when tumor rates were adjusted for early mortality. In female mice, the incidence of alveolar-bronchiolar neoplasms was increased at all exposure concentrations com pared with controls. Thus, even at 6.25 ppm, butadiene is carcinogenic to B6C3Fi mice. The reduced incidence of lung neoplasms at 625 ppm compared with the incidence at 200 ppm is attributed to the high rate of early deaths due to lymphocytic lymphoma in female mice exposed to 625 ppm (Fig. 3). For alveolar-bronchiolar neoplasms, the time to tumor detection was slightly shorter with exposure to 625 ppm; how ever, because all of the female mice exposed to this concentra tion of butadiene died by Wk 65, the final incidence of this neoplastic lesion was less than that for female mice exposed to 200 ppm. Furthermore, the rates of alveolar-bronchiolar neo plasms in early death female mice exposed to 200 or 625 ppm of butadiene were nearly equivalent during 25-wk intervals for the first 75 wk of the study. After that time, a high rate of alveolar-bronchiolar neoplasms (78%) was observed in the 200- ppm exposure group. Mortality-adjusted dose-response curves 6593 VRD 000 20,3 7 125 CARCINOGENICITY OF U-BUTADIENE A Table I Survival and incidence ofprimary tumors in male B6C3F, mice exposed to l.J-butadienefor up to 2 yr Incidence is given as the number of animals bearing a neoplastic lesion at a specific anatomical site. Overall rates, based on the number of animals in which that site was examined, are given below the incidence values. Mortality-adjusted tumor rates are given in parentheses.____________ Exposure concentration (ppm) Initial no.* No. of survivors 0 6.25 20 62.5 200 625 70 70 70 70 70 90 35 39 24* 22* 3* 0* Target (neoplasm) Lymphocytic lymphoma 2 31 (41) 1 11 (21) 2 31 (51) 4 61 (101) 2 31 (71) 62 691 (961) All lymphomas 4 61 (81) 3 41 (61) 8 111 (19%) 11' 161 (251) 9* 131 (271) 69* 771 (971) Heart (hemangiosa/coma) 0 01 (01) 0 01 (01) 1 11 (21) 5* 71 (131) 20* 291 (571) 6* 71 UK) Lung (alveolar-bronchiolar neoplasm) 22 311 (461) 23 381 (481) 20 331 (451) 33* 481 (721) 42* 601 (871) 12* 131 (731) Forestomach (squamous cell neoplasm) Harderian gland (neoplasm) 1 11 CD 6 91 (131) 0 01 (01) 7 101 (151) 1 11 (21) 11 161 (251) 5 71 (131) 24* 341 (531) 12* 171 (361) 33* 471 (771) 13* 141 (751) 7* *1 (581) Preputial gland (adenoma or carcinoma) 0 01 (01) 0 01 (01) 0 0% (01) 0 01 (01) S* 71 (171) 0 01 (01) Liver (hepatocellular neoplasm) 31 441 (551) 27 451 (541) 35 591 (6*1) 32 541 (691) 40* 591 (871) 12 131 (751) * Initial number includes animals removed from the study for interim sacrifices at 40 and 65 wk. * Decreased compared with chamber control <0 ppm). P < 0.0S. * Increased compared with chamber control (0 ppm). P < 0.0$, based on logistic regression analyses with adjustment for imercurrent mortality. for lymphocytic lymphoma, hemangiosarcoma of the heart, and neoplasms of the lung, forestomach, and Harderian gland in female mice are shown in Fig. 4. The sharp and rapid concen tration-dependent increase in the incidence of alveolar-bronchiolar neoplasms in female mice is particularly noteworthy. The estimated rate of alveolar-bronchiolar neoplasms in female mice after adjustment for intercurrem mortality is 8% at 0 ppm (controls), 32% at 6.25 ppm. 44% at 20 ppm, 61% at 62.5 ppm, 81 % at 200 ppm, and 83% at 625 ppm. The incidences of neoplastic lesions of the forestomach (squa mous cell neoplasms), mammary gland (adenocarcinomas), ovary (granulosa cell neoplasms), and liver (hepatocellular neo plasms), the other organ sites identified in the first study (11, 23), were again increased. In addition, the Harderian gland and preputial gland were identified as sites of butadiene-induced neoplasia. The concentrations of butadiene at which these le sions were not significantly increased compared with controls were 62.5 ppm for forestomach squamous cell neoplasms and preputial gland neoplasms, 20 ppm for Harderian gland neo plasms, mammary gland adenocarcinomas, and ovarian gran ulosa cell neoplasms, and 6.25 ppm for hepatocellular neo plasms. In the stop-exposure groups, survival was also markedly reduced due to the development ofcompound-related malignant tumors (Table 3). The tumor incidence profiles in the stop- exposure groups show that lymphocytic lymphomas, hemangiosarcomas of the heart, alveolar-bronchiolar neoplasms, fore stomach squamous cel) neoplasms, Harderian gland neoplasms, and preputial gland neoplasms were increased compared with controls even after only 13 wk of exposure to 625 ppm of butadiene. Furthermore, at comparable total exposures, the incidence of lymphocytic lymphoma was greater with exposure to a higher concentration of butadiene for a short time com pared with exposure to a lower concentration for an extended duration. This is evident by comparing the incidence of lym phocytic lymphoma in the 625-ppm stop-exposure 13-wk group (34%) with that in the 200-ppm stop-exposure 40-wk group (12%), or more notably by comparing the incidence in the 625ppm stop-exposure 26-wk group (60%) with that in the 312ppm stop-exposure 52-wk group (6%). Renal tubular cell ade nomas. which rarely occur in untreated B6C3Fi mice (<0.1%). were also observed at increased rates in the stop-exposure groups at the lower butadiene concentrations. Increased incidences of proliferative, nonneoplastic lesions in the heart (endothelial hyperplasia), lung (alveolar epithelial hyperplasia), forestomach (epithelial hyperplasia). Harderian gland (hyperplasia), and ovary (granulosa cell hyperplasia) probably represent preneoplastic changes caused by butadiene at these target sites, while the distinction between adenoma and carcinoma further reveals the biological progression of chemi cal-induced neoplastic lesions to malignant neoplasia. The spec trum of these proliferative lesions in mice exposed to butadiene is shown in Tables 4 (males) and 5 (females). At each of these sites, the neoplastic responses were generally supported by accompanying increases in the incidences of related nonneo plastic. proliferative lesions. In the lung of male mice, progres sion from alveolar-bronchiolar adenoma to carcinoma was evi dent in the 200-ppm exposure group and in all of the stopexposure groups. In control female mice, only benign neoplastic lesions were observed in the lung, forestomach, Harderian gland, and ovary; however, in female mice exposed to butadiene, malignant neoplasms were observed in these organs. In partic- 6594 9H H H 000 OM CARCINOGENICITY OF 1,3-BUTADIENE Table 2 SunivaJ end incidence ofprimary turnon infernal* B6C3F, mice exposed to 1J-buladien*for up to 2 yr Incidence is given u the number of animals bearing a neoplastic lesion at a specific anatomical site. Overall rales, based on the number of animals in which that site was examined, are given below the incidence values. Mortalily-adjusied tumor rates are given in parentheses, 1 .0 6.25 Exposure concentration (ppm) 20 62.5 200 625 Initial no.* No. of survivor* 70 70 70 70 70 90 37 33 24* 11* 0* 0* Target (neoplasm) Lymphocytic lymphoma 2 375 (4%) 4 6% (%) 6 975 (147*) 3 4% (8%) 11' 16% (41%) AM lymphomas 10 14% (20*5) 14 20% (30%) 18' 26% (41%) 10 14% (26%) ir 2775 (58%) Heart (hemangiosarcoma) 0 0% (0%) 0 0% (075) 0 075 (0%) 1 1% (3%) 20' 29% (64%) Lung | alveolar-bronchiolar neoplasm) 4 6% (875) ir 2575 (32%) 19132% (44%) 2r 39% (61%) 32* 46% (81%) Forestomach (squamous cell neoplasm) 2 375 (475) 2 3% (4%) 3 4% (8%) 4 6% (12%) r 10% (31%) Harderian gland (adenoma or adenocarcinoma) 9 1375 (1875) 10 14% <2175) 7 10% (17%) 16r 23% (40%) ir 31% (67%) Liver (hepatocellular neoplasm) 17 25% (35%) 20 33% (41%) 23' 38% (5275) 24' 40% (60%) 20' 33% (68%) * Mammary gland (adenocarcinoma) 0 075 (0%) 2 375 (4%) 2 3% (5%) 6' 9% (16%) 13' 19% (47%) Ovary (granulosa cel) neoplasm) 1 1% (2%) 0 0% (0%) 0 0% (075) 9* 13% (24%) ir 16% (44%) * Initial number includes animals removed from the stud) for interim sacrifices at 40 and 05 wk. * Decreased compared with chamber control (0 ppm), F < 0.05. ' Increased compared with chamber control (0 ppm), P < 0.05, based on logistic regression analyses with adjustment for intercurrent mortality. 36' 40% (86%) 43' 48% (89%) 26' 29% (8475) 25' 28% (83%) 28' 31% (85%) 7 8% (48%) 3 3% (28%) 13' 14% (66%) 6 7% (44%) . appears to be largely due to the increase in hepatocellular carcinomas. The greater tendency to malignant neoplasia in mice exposed to butadiene further demonstrates the strong carcinogenic potency of this chemical. Squamous cell papillomas and squamous cell carcinomas of the forestomach were detected as late as Wk 88 and Wk 105 in male mice that had been exposed to 625 ppm of butadiene for 13 wk and then held in control chambers to allow time for progression or regression of butadiene-induced lesions. The observation of both benign and malignant neoplasms of the forestomach near the end of the 2-yr studies in mice exposed to butadiene for only 13 wk shows that forestomach lesions induced by butadiene may persist and progress to malignant neoplasms in the absence of further exposure to this carcino genic compound. The high incidences of neoplastic lesions at multiple organ sites in mice exposed to butadiene also resulted in numerous occurrences of animals with tumors at more than one primary WEEKS ON STUDY Fig. 1. Cumulative incidence of lymphocytic lymphomas or hemangiosarcomas of the heart versus weeks on study for mate B6C3F, mice exposed to 300 or 625 ppm of 1,3-butadiene. site. The frequencies of multiple organ site neoplasia in male mice and in female mice are shown in Tables 6 and 7. For these evaluations, lung tumors were not considered for male mice and liver tumors were not considered for female mice because of the high incidences of these neoplastic lesions in the respec ular, high incidences of alveolar-bronchiolar carcinomas were tive control groups. Neoplasms were observed in two or more observed in exposed female mice, even at 6.25 ppm of buta of the designated organ sites in 54% of the female mice and diene. Also, the increased incidence of hepatocellular neoplasms approximately 30% of the male mice exposed to 200 ppm of in female mice exposed to butadiene compared with controls butadiene. Eight female mice developed primary tumors at 4 6595 CARCINOGENICITY OF l.l-BLTADIENE A VRD 0002037127 EXPOSURE CONCENTRATION fPPMl EXPOSURE CONCENTRATION (PPM) Fig. 2. Dose-response curvet for Ivmphocvtk lymphomas (O). hemangiosarcomas of ihe heart <G). aheolar-bronchiolar neoplasms (A). Harderian gland neoplasms (A), and squamous cell neoplasms of the foresiomach {> in male B6C3F| mice exposed to 1.3-butadiene. Results from the 312-ppm. 52-wk stopexposure group are also included, because that was the longest exposure duration of the stop-exposure groups and the incidence of lymphocy tic lymphoma was not increased in that group compared with controls. Mortality-adjusted tumor races were determined by the method of Portier and Bailer (20) using a power value equal to 3 (21). Fig. 4. Dose-rciponsc curves for lymphocytic lymphomas (O). hemangiosarcomas of the heart (). alveolar-bronchiolar neoplasms (A). Harderian gland neoplasms (A), and squamous cell neoplasms of the forestomach (B) in female B6C3F, mice exposed to 1.3-butadiene. Mortality-adjusted tumor rates were determined by the method of Portier and Bailer (20) using a power value equal to 3 (21). In male or female mice exposed to 625 ppm of butadiene, or in female mice exposed to 200 ppm, competing risks of early occurring lethal thymic lymphomas limited the detection of later developing neoplasms at other organ sites. However, by - 50 r adjusting for intercurrent mortality or by comparing tumor rates in early death animals at discrete time intervals of the study, it was possible to account for the influence of reduced survival resulting from induction of lymphocytic lymphoma on the dose responses of the later appearing tumors. At lower exposure concentrations where lymphocytic lymphoma was not a major cause of early death, (he incidences of neoplastic lesions in the heart, lung, forestomach, Harderian gland, preputial gland, liver, mammary gland, and ovary were nearly linearly related to the concentration of butadiene. In the lungs of female mice, alveolar-bronchiolar carcinomas were induced at the low est exposure concentration of 6.25 ppm ofbutadiene. Malignant lung tumors are uncommon in untreated female B6C3F, mice Fig. 3. Cumulative incidence of lymphocytic lymphomas or alveolar-bronchiolar neoplasms versus weeks on study for female B6C3Fi mice exposed to 200 or 625 ppm of 1.3-butadiene. (26) and were not observed in control female mice in this study. Thus, butadiene is carcinogenic in mice at concentrations which are less than those to which humans are potentially exposed in occupational settings (4). different organ sites, while one female mouse had 5 different The stop-exposure studies show that multiple organ site primary sites of tumor development. neoplasia occurs in mice after only 13 wk of exposure to butadiene. It is likely that shorter exposure durations would DISCUSSION also produce a positive carcinogenic response. These studies also demonstrate that butadiene-induced forestomach lesions The present studies demonstrate that 1.3-butadiene is a po can persist for long periods of time after exposure has ceased tent multiple organ carcinogen in mice and is carcinogenic at and may progress to malignant neoplasms. The development all concentrations evaluated, ranging from 6.25 to 625 ppm. of thymic lymphomas in mice exposed to butadiene is not Because there were no exposure concentrations in these studies equivalent under different exposure regimens which result in that did not result in carcinogenicity, the possibility exists that the same total exposure; the stop-exposure studies show that exposure levels below 6.25 ppm will also cause cancers in the concentration of butadiene is a much greater contributing laboratory animals. The concentrations of butadiene used in factor than is the duration of exposure. Likewise, time-w eighted these studies are within the linear range of metabolic elimina average exposures to butadiene in the workplace may not ac tion of butadiene in B6C3F( mice (24). Miller and Boorman curately reflect the potential human risk of cancer. (25) have provided morphological descriptions and illustrations The mechanism of butadiene-induced carcinogenicity is not of neoplastic and nonneoplastic lesions induced by 1,3-buta known; however, butadiene monoxide and/or diepoxybutane, diene in B6C3F( mice. oxidative intermediates of butadiene biotransformation (7), is 6596 CARCINOGENICITY OF 1,3-BUTADIENE Table 3 Survival and incidence ofprimary tumors in the stop-exposure groups of male 86C3F, mice exposed to l.S-butadiene Incidence is given as the number of animals bearing a neoplastic lesion at a specific anatomical site. Overall rates, based on the number of animals in which that te was examined, are given below the incidence values. Mortality-adjusted tumor rates are given in parentheses. Exposure concentration (ppm) - Initial no * No. of survivors 0 Control 70 35 200 Stop-exposure 40 wk 18.000)' 50 9' 625 Stop-exposure 13 wk (8.125) 50 5f 312 Stop-exposure 52 wk (16.224) 50 1' 625 Slop-exposure 26 wk (16.250) 50 O' Target (neoplasm) Lymphocytic lymphoma 2 35 (45) 6 125 (195) 17' 345 (475) 3 65 (155) 30605 (845) All lymphomas 4 6T (85) 12' 245 (355) 24' 485 (615) 15' 305 (555) 37' 745 (905) Heart (hemangiosarcoma) 0 05 <o*> 15' 305 (475) 7' 145 (315) 33' 665 (875) 13' 265 (765) Lung (alveolar-bronchiolar neoplasm) 22 315 (46 5) 35' 705 (885) 27' 545 (875) 32' 645 (885) 18' 365 (895) Forestomach (squamous cell neoplasm) Harderian gland (adenoma or adenocarcinoma) I 15 12*1 6 95 (135) 6' 125 (205) 27' 545 (725) 8' 165 (335) 23' 465 (825) 13' 265 (525) 28' 565 (865) II' 225 (635) II' 225 (705) Preputial gland (carcinoma) 0 05 (05) 1 25 (35) 5' 105 (215) 4' 85 (215) 3' 65 (315) Kidney (renal tubular adenoma) 0 05 (05) y' 105 (165) 1 25 (55) 3' 65 (155) 15 25 (115) * Total exposure expressed as ppm-wk. * Initial number ofcontrol mice includes 20 animals removed from the study for interim sacrifices at 40 and 65 wk. c Decreased compared with chamber control <0 ppm), P < 0.05. ' Increased compared with chamber control (0 ppm). P < 0.05. based on logistic regression analyses with adjustment for intercurrent mortality. Table 4 Incidence of nonneopiastic lesions and neoplastic lesions in the heart, lung, forestomach, and Harderian gland ofmate mice exposed to 1.3-butadiene Exposure concentration (ppm) Site and lesion Heart Endothelial hvperplasia Hemangiosarcoma Lung Alveolar epithelial hyperplasia Alveolar-bronchiolar adenoma Aheolar-bronchiolar carci noma 0 (70)' 0 0 (70) 1 14 9 6.25 (49) l 0 (49) 5 14 13 20 (60) 0 (60) 4 II 11 62.5 (58) 3 5* (69) 12 23* 15 200 168) 8 20* (70) 19 25* 24* 625 (90) 8 6* (89) 18 10* 5 200 Stop-exposure 40 wk (50) 6 15* (50) 13 19* 22* 625 Stop-exposure 13 wk (50) 7 7* (50) 11 13* 20* 312 Stop-exposure 52 wk (501 3 33* (501 13 24* 16* 625 Stop-exposure 26 wk (50) 6 13* (50) 10 11* II* Forestomach Epithelial hyperplasia Squamous cell papilloma Squamous cell carcinoma (70) 4 1 0 (50) (60) (60) (68) (89) 3 2 4 3 47 0 1 5 9* 9* 0 0 0 3 4* (48) 7 6* 0 (50) 8 5* 4* (48) 16 8* S* (50) 16 4* 7* Harderian gland Hyperplasia Adenoma Adenocarcinoma (63) 1 6 0 (59) (60) (57) (60) (53) 34497 7 10 23* 32* 7* 1 1 220 (48) X 26* 2 (42) 2 20* 4* (48) 7 26* 2 * Numbers in parentheses are the number of animals in which that site was examined microscopically. * Increased compared with chamber control (0 ppm). P < 0.05, based on logistic regression analyses with adjustment for intercurrent mortality. (36) 8 11* 0 likely involved. These metabolites are direct acting mutagens in 5. typhimurium (8. 9). whereas the detection of mutagenicity of butadiene requires metabolic activation (6). Furthermore, these epoxides have been shown to induce "local" (application site) neoplasms when applied to the skin of Swiss mice or when administered to Swiss mice or Sprague-Dawtey rats by s.c. injection (27. 28). Also, exposure of B6C3F| mice to 1250 ppm of butadiene did not result in any persistent defects in humoral or cell-mediated immunity (29). In groups of 100 Sprague-Dawley rats exposed to 1000 or 8000 ppm of 1.3-butadiene for 2 yr. Owen et at. (12) reported that there were increased incidences and dose-response trends 6597 A VRD 0002037128 CARCINOGENICITY OF I.JBUTaOIENE A VRD 000203712? Table S Incidence of nonneoptasnc lesions and neoplastic lesions in the heart, lung, forestomach, Harderian gland, liver, and ovary offemale mice exposed to 1,3-butadiene Exposure concentration (ppm) Site and ksion Heart Endothelial hyperplasia Hemangiosarcoma 0 6.25 20 62.5 200 625 <70>' (50) (50) (59) (70) (90) 0 2 1 4 12 10 0 0& 1 20* 26* Lung Alveolar epithelial hyperplasia Alveolar-bronchiolar adenoma Alveolar-bronchiotar carcinoma (70) (60) (60) (70) (70) (88) 6 4 6 11 13 11 4 g 10* 18* 20* 14* 0 8* 13* 10* 20* 12* Forestomach Epithelial hyperplasia Squamous cell papilloma Squamous cell carcinoma Harderian gland Hyperplasia Adenoma Adenocarcinoma (70) 2* 2 0 (63) 1 9 0 (50) (57) (68) (70) (89) 3 4 6 16 48 1 2 3 6* 22* 1 1 l 1 6* 149) (48) (59) (59) (73) 39 1 49 9 6 16* 22* 7 1 1 010 Liver Hepatocellular adenoma Hepatocellular carcinoma (69) (51) (51) (60) (60) (90) 12 9 14 15* 13* 2 7 13 11 11* 12* 1 Ovary Granulosa cell hyperplasia Granulosa cell tumor, benign Granulosa cell tumor, malignant (69) 0 1 0 (59) (59) (70) (70) (89) 2 1 474 00 7* 8* 6 0 0 2 3* 0 * Numbers in parentheses are the number of animals in which that site was examined microscopically. * Increased compared with chamber control (0 ppm). P < 0.05. based on logistic regression analyses with adjustment for intercurrent mortality. Table 6 Frequency of multiple-site neoplasia in male B6C3F, mice exposed to 1.3-butadiene: lymphocytic lymphoma: hemangiosarcoma ofthe heart: squamous cell neoplasm of the forestomach: and Harderian gland neoplasm No. of organ sites/animal Exposure group 0 Control 6.25 ppm 20 ppm 62.5 ppm 200 ppm 625 ppm 200 ppm: stop-exposure. 40 wk 625 ppffl: stop-exposure. 13 wk 312 ppm; stop-exposure. 52 wk 625 ppm; stop-exposure, 26 wk 62 (89)* 52 (87) 47 (78) 36 (52) 27 (39) 15(17) 15(30) 8(16) 4(8) 5(10) a Numbers in parentheses, percentage. 12 .Vo. ofanimals 7(10) 8(13) 12(20) 28(41) 23(33) 65 (72) 20|40) 1(1) 0 1 (2) 5(7) 16(23) 7(8) 10(20) 32 (64) 8(16) 22 (44) 17(34) 27 (54) 16(32) 3 0 0 0 0 4(6) 3(3) 5(10) 2(4) 7(14) 2(4) Table 7 Frequency ofmultiple-site neoplasia in female B6C3F, mice exposed to 3-butadiene: lymphocytic lymphoma; hemangiosarcoma of the heart; aiveoiarbronchiotar neoplasm: squamous cell neoplasm of theforestomach: Harderian gland neoplasm; adenocarcinoma of the mammary gland: and granulosa cell neoplasm of the ovary Exposure group No. of organ sites/animal ____i--------------------------------------------------------------------------------- 0 1 2 3 45 Control 6.25 ppm 20 ppm 62.5 ppm 200 ppm 625 ppm 55 (79)J 34 (57) 31 (52) 27 (39) 13(19) 17(19) <Vo. ofanimals 12(17) 19(32) 22 (37) 24 (34) 19(27) 29(32) 3(4) 7(12) 6(10) 16(23) 20(29) 26 (29) 0 0 (2) 2(3) 15(21) 13(14) 0 0 0 1 (1) 3(4) 4(4) 0 0 0 0 0 1 (1) ' Numbers in parentheses, percentage. for pancreatic exocrine adenomas (control, 3; low dose, one; high dose. 10) and Leydig cell neoplasms of the testis (control. 0; low dose. 3; high dose, 8) in males and uterine sarcomas (control, one; low dose, 4; high dose, 5), Zymbal gland carci nomas (control, 0; low dose, 0; high dose, 4), mammary gland neoplasms (control. 50; low dose. 79; high dose. 81). and thyroid follicular cell neoplasms (control, 0; low dose. 4; high dose. II) in females. The sites of tumor induction and the magnitude of response in rats were different from those re ported here for B6C3F! mice. The reason for this species difference is not known; however, it is not readily accounted for by differences in rates of butadiene metabolism (23). Irons and coworkers (30, 31) compared the induction of thymic lymphomas in NIH Swiss mice and B6C3F, mice ex posed to butadiene and suggested that activation of an endog enous ecotropic retrovirus may play a role in butadiene-induced lymphoma in the B6C3F, strain of mice. The NIH Swiss mouse rarely expresses endogenous retrovirus and has a background rate of zero for thymic lymphoma. Thus, the finding that exposure of NIH Swiss mice to 1250 ppm of butadiene for 1 yr caused a 14% incidence of thymic lymphoma (31) indicates that butadiene can induce this neoplasm independently of an acti vated retrovirus. The conclusion that the marginally increased incidences of hepatocellular neoplasms in male and female mice were chem ically related is strengthened by the detection of an activated K-roj oncogene in liver neoplasms obtained from mice exposed to butadiene (32); activated K-ras has never been detected in liver tumors from untreated B6C3F, mice (33). Exposure to butadiene also caused activation of the K-ras oncogene in mouse lymphomas and lung neoplasms. These findings add further relevance to the potential carcinogenicity of butadiene in hu mans, since K-r<w is the most commonly detected oncogene in human tumors. Other toxic effects associated with exposure of mice to bu tadiene. and relevant to humans, include testicular atrophy in males exposed to 625 ppm, ovarian atrophy in females exposed to 6.25 ppm or higher concentrations, and bone marrow toxicity at 62.5 ppm and higher concentrations (34). The carcinogenicity of butadiene in laboratory animals at concentrations as low as 6.25 ppm and the activation of the Kras oncogene by butadiene raise further concerns of risk for humans exposed to this chemical. Results of epidemiology studies indicate an association between occupational exposure to 1.3-butadiene and the development of lymphatic and hema topoietic cancers (15. 16); for example, standardized mortality ratios were 500% for lymphopoietic cancers and 660% for leukemia in black production workers (15). In a follow-up nested case-control study of the styrene-butadiene rubber in dustry, Matanoski ei ai. (35) found that leukemia cases were associated with exposure specifically to butadiene (odds ratio, 9.4; 95% confidence interval, 2.1-22.9), whereas there was not a significant increased risk associated with exposure to styrene. Because of the correspondence between the animal data and the epidemiology findings, there exists an urgent worldwide public health need to reevaluate current workplace exposure standards for 1,3-butadiene. ACKNOWLEDGMENTS The authors thank Dr. Joseph Haseman for providing the mortality- adjusted tumor rates and Dr. John Bucher and Dr. Michael Elwell for reviewing this manuscript. H U 1 9 U 8 9 (IXA CARCINOGENICITY OF 1.3-HLTADIENE REFERENCES . Kirshenboum. I. Butadiene. In: Kirk-Othmer Encyclopedia ofChemical Tech nology. Ed. 3. Vol. 4. pp. 313-33-7. Ne York: John Wiley & Sons. 1979. 2. Morrow, N. L. The industrial production and use of 1.3-butadiene. Environ. Health Perspect.. 86: 7-8. 1990. 3. UniietLStates Environmental Protection Agency. 1.3-Butadiene: decision to report to the Occupational Safety and Health Administration. Federal Regier, 50: 41393-41398. 1985. 4. Fajen. J. M.. Roberts. D. R.. Ungers, L. J., and Krishnan. E. R. Occupational exposure of workers to 1.3-butadiene. Environ. Health Perspect.. 86:11-18. 1990. 5. Miller. L. M. Investigation of selected potential environmental contaminants: butadiene and its oligomers. In: EPA-560/2-78-008. Washington. DC: US Environmental Protection Agency. 1978. 6. DeMeesier. C.. Poncelei. F.. Roberfroid. M.. and Mercier. M. The mutagen icity of butadiene towards Salmonella typhimurium. Toxicol. Lett.. 6: 125- 130. 1980. 7. Malvoisin, E.. and Roberfroid. M. Hepatic microsomal metabolism of 1.3- butadiene. Xenobiotica. 12:137-144,1982. 8. DeMeester, C.. Poncelet, F.. Roberfroid, M.. and Mercier. M. Mutagenicity of butadiene and butadiene monoxide. Biochem. Biophys. Res. Commun.. 80: 298-305. 1978. 9. Wade. M. J.. Moyer. J. W., and Hine. C. H. Mutagenic action of a series of epoxides. Mutat. Res.. 66: 367-371. 1979. 10. Tice. R. R.. Boucher. R.. Luke. C. A., and Shelby. M. D. Comparative cytogenetic analysis of bone marrow damage induced in male B6C3Fi mice by multiple exposures to gaseous 1,3-butadtene. Environ. Mutagen.. 9: 235250. 1987. 11. Huff. J. E,, Melnick. R. L.. Solleveld. H. A.. Hascman. J. K.. Powers, M., and .Miller. R. A. Multiple organ carcinogenicity of 1.3-butadiene in B6C3F, mice after 60 weeks of inhalation exposure. Science (Wash. DC). 222: 548549. 1985. 12. Owen. P. E.. Glaister, J. R., Gaunt. I. F.. and Pullinger, D. H. Inhalation toxicity studies with 1.3-butadiene. 3. Two-year toxicity/carcinogenicity Study in rats. Am. Ind. Hyg. Assoc. J., 48: 407-413. 1987. 13. American Conference of Governmental Industrial Hygienists. Threshold Limit Values for Chemical Substances and Physical Agents in the Workroom Environment and Biological Exposure Indices with Intended Changes for 1984-1985. Cincinnati. OH. 1984. 14. Grossman, E. A., and Martonik. J. OSHA's approach to risk assessment for setting a revised occupational exposure standard for 1,3-buladiene. Environ. Health Perspect., 86:155-158. 1990. 5. Matanoski. G. M.. Santos-Burgoa, C.. and Schwartz. L. Mortality of a cohort of workers in the styrene-butadiene polymer (SBR) manufacturing industry 1943-1982. Environ. Health Perspect.. 86: 107-117. 1990. 16. Divine. B. J. An update on mortality among workers at a butadiene facility-- preliminary results. Environ. Health Perspect.. 86: 119-128, 1990. 17. Cox, D. R. Regression models and life tables. J. R. Stat. Soc.. B34: 187-220. 1972. 18. Cart. J. J.. Chu. K. C., and Tarone. R. E. Statistical issues in interpretation of chronic bioassay tests for carcinogenicity. J. Natl. Cancer Inst.. 62: 957974, 1979. 19. Dinse. G. E.. and Haseman. J. K. Logistic regression analysis of incidental tumor data from animal carcinogenicity experiments. Fund. Appl. Toxicol.. 6.44-52. 1986. 20. Portier. C. J., and Bailer. A. J. Testing for increased carcinogenicity using a survival-adjusted quanta! response test. Fund. Appl. Toxicol.. 12: 731-737. 1989. 21. Portier, C. J.. Hedges. J. C.. and Hoel, D. G. Age-specific models of mortality and tumor onset for historical control animals in the National Toxicology Program's carcinogenicity experiments. Cancer Res.. 46: 4372-4378, 1986. 22. Frith. C. H.. and W iley, L. D. Morphologic classification and correlation of incidence of hyperplastic and neoplastic hematopoietic lesions in mice with age. J. Gerontol., 5: 534-545, 1981. 23. National Toxicology Program. Toxicology and carcinogenesis studies of 1.3butadiene (CAS No. 106-99-0) in B6C3F| mice (inhalation studies). In: NTP TR No. 288. pp. I-111. Bethesda, MD. National Institutes of Health, 1984. 24. Kreiling. R.. Laib, R. J., Filser, J. G., and Bolt. H. M. Species differences in butadiene metabolism between mice and rats evaluated by inhalation phar macokinetics. Arch. Toxicol., 58: 235-238. 1986. 25. Miller. R. A., and Boorman, G. A. Morphology of neoplastic lesions induced by 1,3-butadiene in B6C3F, mice. Environ. Health Perspect., 86: 37-48. 1990. 26. Haseman. J. K,, Huff. J. E.. Rao, G. N.. Arnold. J. E.. Boorman, G. A., and McConnell. E. E. Neoplasms observed in untreated and corn oil gavage control groups of F344/N rats and (C57BL/6N x C3H/HeN)F, (B6C3F,) mice. J. Natl. Cancer Inst.. 75:975-984.1985. 27. Van Duuren, B. L., Nelson, N., Orris. L.. Palmes. E. D.. and Schmitt. F. L. Carcinogenicity of epoxides, lactones, and peroxy compounds. J. Natl. Can cer Inst.. 31: 41-55, 1963. 28. Van Duuren. B. L.. Langsclh. L.. Orris, L.. Teebor. G-. Nelson. N., and Kuschncr. M. Carcinogenicity of epoxides, lactones, and peroxy compounds. IV. Tumor response in epithelial and connective tissue in mice and rats. J, Nail. Cancer Inst.. 37:825-838.1966. 29. Thurmond. L. M.. Lauer. L. D.. House. R. V.. Stillman. W. S.. Irons, R. D., Steinhagcn. W. H.. and Dean. J. H. Effects of short-term inhalation exposure to 1.3-butadicne on murine immune functions. Toxicol. Appl. Pharmacol., 86: 170-179. 1986. 30. Irons, R. D., Stillman. W. S.. and Cloyd, M. W. Selective activation of endogenous ecotropic retrovirus in hematopoietic tissues of B6C3F) mice during the preleukemic phase of 1.3-butadiene exposure. Virology. 161: 457462. 1987. 31. Irons. R. D. Studies on the mechanism of 1.3-butadiene-induced leukemogenesis: the potential role of endogenous murine leukemia virus. Environ. Health Perspect.. 86: 49-55, 1990. 32. Goodro*. T., Reynolds. S.. Maronpot. R.. and Anderson. M. Activation of K-rrnby codon 13 mutations in C57BL/6 x C3HF, mouse tumors induced by exposure to 1,3-butadiene. Cancer Res.. 50:4818-4823. 1990. 33. Reynolds.S. H..Stowers. S. J.. Patterson.R. M., Maronpot. R. R.. Aaronson. S. A., and Anderson. M. W. Activated oncogenes in B6C3Ft mouse liver tumors: implications for risk assessment. Science (Wash. DC). 237: 1309- 1316. 1987. 34. Melnick. R. L., HufT. J. E.. Roycroft. J. H.. Chou. B. J.. and Miller, R. A. Inhalation toxicology and carcinogenicity of 1.3-butadiene in B6C3F, mice following 65 weeks of exposure. Environ. Health Perspect.. 86: 27-36, 1990. 35. Matanoski. G. M-. Santos-Burgoa, C., Zeger. S. L.. and Schwartz. L. Epi demiologic data related to health effects of 1.3-butadiene. In: U. Mohr, D. V. Bates. D. L. Dungworth. P. N. Lee, R. O. McCellan. and F. J. C. Roe (eds.). Assessment of Inhalation Hazards, pp. 201-214. New York: Springer- Verlag, 1989. A 6599 B 1,3-BUTADIENE . -- Q U.S. DEPARTMENT OF HEALTH & HUMAN SERVICES TOXICOLOGICAL PROFILE FOR 1,3-BUTADIENE Prepared by: Syracuse Research Corporation Under Subcontract to: Clement International Corporation Under Contract No. 205-88-0608 Prepared for: Agency for Toxic Substances and Disease Registry U.S. Public Health Service July 1992 I E L 018 203 7133 ii DISCLAIMER. The use of company or product name(s) is for identification only and does not imply endorsement by the Agency for Toxic Substances and Disease Registry. VRD 0802037134 iii FOREWORD The Superfund Amendments and Reauthorization Act (SARA) of 1986 (Public Law 99-499) extended and amended the Comprehensive Environmental Response, Compensation, and Liability Act of 1980 (CERCLA or Superfund). This public law directed the Agency for Toxic Substances and Disease Registry (ATSDR) to prepare toxicological profiles for hazardous substances which are most commonly found at facilities on the CERCLA National Priorities List and which pose the most significant potential threat to human health, as determined by ATSDR and the Environmental Protection Agency (EPA). The lists of the 250 most significant hazardous substances were published in the Federal Register on April 17, 1987; on October 20, 1988; on October 26, 1989; and on October 17, 1990. A revised list of 275 substances was published on October 17, 1991. Section 104(i)(3) of CERCLA, as amended, directs the Administrator of ATSDR to prepare a toxicological profile for each substance on the lists. Each profile must include the following content: (A) An examination, summary, and interpretation of available toxicological information and epidemiological evaluations on the hazardous substance in order to ascertain the levels of significant human exposure for the substance and the associated acute, subacute, and chronic health effects. (B) A determination of whether adequate information on the health effects of each substance is available or in the process of development to determine levels of exposure which present a significant risk to human health of acute, subacute, and chronic health effects. (C) Where appropriate, an identification of toxicological testing needed to identify the types or levels of exposure that may present significant risk of adverse health effects in humans. This toxicological profile is prepared in accordance with guidelines developed by ATSDR and EPA. The original guidelines were published in the Federal Register on April 17, 1987. Each profile will be revised and republished as necessary. The ATSDR toxicological profile is intended to characterize succinctly the toxicological and adverse health effects information for the hazardous substance being described. Each profile identifies and reviews the key literature (that has been peer-reviewed) that describes a hazardous substance's toxicological properties. Other pertinent literature is also presented but described in less detail than the key studies. The profile is not intended to be an exhaustive document; however, more comprehensive sources of specialty information are referenced. A ii ]1 (t VRD 0002037135 Foreword iv Each toxicological profile begins with a public health statement, which describes in nontechnical language a substance's relevant toxicological properties. Following the public health statement is information concerning levels of significant human exposure and, where known, significant health effects. The adequacy of information to determine a substance's health effects is described in a health effects summary. Data needs that are of significance to protection of public health will be identified by ATSDR, the National Toxicology Program (NTP) of the Public Health Service, and EPA. The focus of the profiles is on health and toxicological information; therefore, we have included this information in the beginning of the document. The principal audiences for the toxicological profiles are health professionals at the federal, state, and local levels, interested private sector organizations and groups, and members of the public. This profile reflects our assessment of all relevant toxicological testing and information that has been peer reviewed. It has been reviewed by scientists from ATSDR, the Centers for Disease Control, the NTP, and other federal agencies. It has also been reviewed by a panel of nongovernment peer reviewers. Final responsibility for the contents and views expressed in this toxicological profile resides with ATSDR. William L. Roper, M.D., M.P.H. Administrator Agency for Toxic Substances and Disease Registry V CONTENTS FOREWORD......................................................................................................................................................................................................iii LIST OF FIGURES............................................................................................................................................................................ in LIST OF TABLES.................................... xi 1. PUBLIC HEALTH STATEMENT ...................................................................................................................................... 1.1 WHAT IS 1,3-BUTADIENE?.......................................................................................................................... 1.2 HOW MIGHT I BE EXPOSED TO 1,3 - BUTADIENE?................................................................... 1.3 HOW CAN 1,3-BUTADIENE ENTER AND LEAVE MY BODY?................................................. 1.4 HOW CAN 1,3-BUTADIENE AFFECT MY HEALTH? ................................................................... 1.5 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED TO 1,3-BUTADIENE? ............................................................................................................... 1.6 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT HUMAN HEALTH? ........................................................................................................................... 1.7 WHERE CAN I GET MORE INFORMATION?...................................................................................... 1 1 2 3 3 4 4 4 2. HEALTH EFFECTS ............................................................................................................................................................... 2.1 INTRODUCTION ......................................................................................................................................................... 2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE..................................... 2.2.1 Inhalation Exposure ............................................................................................................... 2.2.1.1 Death ......................................................................................................................... 2.2.1.2 Systemic Effects ............................................................................................ 2.2.1.3 ImmunologicalEffects ............................................................................. 2.2.1.4 Neurological Effects ................................................................................ 2.2.1.5 Developmental Effects .......................................................................... 2.2.1.6 Reproductive Effects ................................................................................ 2.2.1.7 Genotoxic Effects ...................................................................................... 2.2.1.8 Cancer .......................................................................................................................... 2.2.2 Oral Exposure................................................................................................................................ 2.2.2.1 Death ........................................................................................................................... 2.2.2.2 Systemic Effects . ..................................................................................... 2.2.2.3 Immunological Effects ......................................................................... 2.2.2.4 Neurological Effects ............................................................................... 2.2.2.5 DevelopmentalEffects ............................................................................. 2.2.2.6 Reproductive Effects ............................................................................... 2.2.2.7 2.2.2.8 Genotoxic Effects ...................................................................................... Cancer .......................................................................................................................... 2.2.3 Dermal Exposure........................................................................................................................... 2.2.3.1 Death.......................................................................................................................... 2.2.3.2 Systemic Effects ............................................................................................ 2.2.3.3 Immunological Effects .......................................................................... 2.2.3.4 Neurological Effects ................................................................................ 2.2.3.5 Developmental Effects .......................................................................... 2.2.3.6 Reproductive Effects................................................................................ 2.2.3.7 Genotoxic Effects ...................................................................................... 2.2.3.8 Cancer........................................................................................................................... 5 5 5 6 6 7 17 17 18 19 19 20 22 22 22 22 22 22 22 22 22 22 22 22 22 22 23 23 23 23 0002037136 30 CT> VRD 0002037137 vi 2.3 2.4 2.5 2.6 2.7 2.8 2.9 TOXICOKINETICS.................................................................................................................................................... 2.3.1 Absorption . ............................................................................................................................. 2.3.1.1 Inhalation Exposure................................................................................ 2.3.2 2.3.1.2 Oral Exposure.................................................................................................. 2.3.1.3 Dermal Exposure........................................................................................... Distribution.................................................................................................................................. 2.3.2.1 Inhalation Exposure ................................................................................. 2.3.2.2 Oral Exposure................................................................................................... 2.3.2.3 Dermal Exposure ............................................................................................ 2.3.3 Metabolism........................................................................................................................................ 2.3.4 Excretion.............................................................................................................................................. 2.3.4.1 Inhalation Exposure ................................................................................. 2.3.4.2 Oral Exposure................................................................................................... 2.3.4.3 Dermal Exposure ............................................................................................. RELEVANCE TO PUBLIC HEALTH................................................................................................................ BIOMARKERS OF EXPOSURE AND EFFECT....................................................................................... 2.5.1 Biomarkers Used to Identify and/or Quantify Exposure to 1,3-Butadiene .................................................................................................................................. 2.5.2 Biomarkers Used to Characterize Effects Caused by 1,3-Butadiene .................................................................................................................................. INTERACTIONS WITH OTHER CHEMICALS....................................................................................... POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE.............................................................. MITIGATION OF EFFECTS............................................................................................................................ ADEQUACY OF THE DATABASE...................................................................................................................... 2.9.1 Existing Information on Health Effects of 1,3-Butadiene . 2.9.2 Data Needs........................................................................................................................................ 2.9.3 On-going Studies ...................................................................................................................... 23 23 23 23 23 24 24 24 24 24 27 27 27 27 27 37 38 38 38 38 39 40 40 42 46 3. CHEMICAL AND PHYSICAL INFORMATION......................................................................................................... 3.1 CHEMICAL IDENTITY ........................................................................................................................................ 3.2 PHYSICAL AND CHEMICAL PROPERTIES............................................................................................. 49 49 49 4. PRODUCTION, IMPORT, USE, AND DISPOSAL............................................................................................. 4.1 PRODUCTION................................................................................................................................................................ 4.2 IMPORT/EXPORT.................................................................................................................................................... 4.3 USE................................................................................................................................................................................... 4.4 DISPOSAL....................................................................................................................................................................... 53 53 57 57 57 5. POTENTIAL FOR HUMAN EXPOSURE...................................................................................................................... 5.1 OVERVIEW....................................................................................................................................................................... 5.2 RELEASES TO THE ENVIRONMENT.......................................................................................................... 5.2.1 Air................................................................................................................................................................. 5.2.2 Water.......................................................................................................................................................... 5.2.3 Soil.......................................................................................................................................................... 5.3 ENVIRONMENTAL FATE........................................................................................................................................ 5.3.1 Transport and Partitioning ....................................................................................... 5.3.2 Transformation and Degradation ........................................................................... 5.3.2.1 Air.................................................................................................................................. 5.3.2.2 Water............................................................................................................................ 5.3.2.3 Soil.................................................................................................................................. 59 59 62 62 63 64 64 64 65 65 67 67 Vll 5.4 5.5 5.6 5.7 LEVELS MONITORED OR ESTIMATED INTHE ENVIRONMENT.............................................. 5.4.1 Air................................................................................................................................................................ 5.4.2 Water....................................."................................................................................................................. 5.4.3 Soil.......................................................................................................................................................... 5.4.4 Other Environmental Media ............................................................................................. GENERAL POPULATION AND OCCUPATIONALEXPOSURE.......................................................... POPULATIONS WITH POTENTIALLY HIGHEXPOSURES........................................................... ADEQUACY OF THE DATABASE..................................................................................................................... 5.7.1 Data Needs.................................................................................................. 5.7.2 On-going Studies ..................................................................................................................... 69 69 71 71 71 72 73 76 76 78 6. ANALYTICALMETHODS...................................................................................................................................................... 6.1 BIOLOGICAL MATERIALS................................................................................................................................. 6.2 ENVIRONMENTAL SAMPLES........................................................................................................................... 6.3 ADEQUACY OF THE DATABASE..................................................................................................................... 6.3.1 Data Needs....................................................................................................................................... 6.3.2 On-going Studies ..................................................................................................................... 79 79 80 82 82 83 7. REGULATIONS ANDADVISORIES.............................................................................................................................. 85 8. REFERENCES............................................................................................................................................................................ 87 9. GLOSSARY..........................................................................................................................................................................................109 APPENDICES A. USER'S GUIDE.................................................................................................................................................................A-l B. ACRONYMS, ABBREVIATIONS, AND SYMBOLS.......................................................................................B-l C. PEER REVIEW.................................................................................................................................................................C-l 0002037138 30 VRD 0082037139 ix LIST OF FIGURES 2-1 Levels of Significant Exposure to 1,3-Butadiene - Inhalation ... 12 2-2 Microsomal Metabolic Pathway of 1,3-Butadiene in Rats .................................... 25 2-3 Existing Information on Health Effects of 1,3-Butadiene ............................... 41 5-1 Frequency of NPL Sites with 1,3-Butadiene Contamination ............................... 61 5-2 Catabolic Pathway for the Biodegradation of 1,3-Butadiene by Nocardia Cultures in Aqueous Media ........................................................................................... 68 VRD 00ff20 57140 xi LIST OF TABLES 2-1 Levels of Significant Exposure to 1,3-Butadiene - Inhalation .... 8 2-2 Genotoxicity of 1,3-Butadiene InVitro ................................................................................. 33 2- 3 Genotoxicity of 1,3-Butadiene InVivo .................................................................................. 34 3- 1 Chemical Identity of 1,3-Butadiene ........................................................................................... 50 3- 2 Physical andChemical Properties of 1,3-Butadiene ................................................... 51 4- 1 Current U.S. Producers of 1,3-Butadiene ................................................................................... 54 4- 2 Facilities That Manufacture or Process 1,3-Butadiene .................................... 55 5- 1 Releases to the Environment from Facilities That Manufacture or Process 1,3-Butadiene ........................................................................................................................... 60 5-2 Detection of 1,3-Butadiene in Air.................................................................................................. 70 5-3 Industrial Workers Potentially Exposed to 1,3-Butadiene ..................................... 74 5- 4 Air Concentrations of 1,3-Butadiene in a Styrene Butadiene Rubber Plant ................................................................................................................................................................ 75 6- 1 Analytical Methods for Determining 1,3-Butadiene in Environmental Samples ....................................................................................................................................... 81 7- 1 Regulations and Guidelines Applicable to 1,3-Butadiene ............................... 86 1 1. PUBLIC-HEALTH STATEMENT This Statement was prepared to give you information about 1,3-butadiene and to emphasize the human health effects that may result from exposure to it. The Environmental Protection Agency (EPA) has identified 1,177 sites on its National Priorities List (NPL). 1,3-Butadiene has been found at 3 of these sites. However, we do not know how many of the 1,177 NPL sites have been evaluated for 1,3-butadiene. As EPA evaluates more sites, the number of sites at which 1,3-butadiene is found may change. The information is important for you because 1,3-butadiene may cause harmful health effects and because these sites are potential or actual sources of human exposure to 1,3-butadiene. When a chemical is released from a large area, such as an industrial plant, or from a container, such as a drum or bottle, it enters the environment as a chemical emission. This emission, which is also called a release, does not always lead to exposure. You can be exposed to a chemical only when you come into contact with the chemical. You may be exposed to it in the environment by breathing, eating, or drinking substances containing the chemical or from skin contact with it. If you are exposed to a hazardous substance such as 1,3-butadiene, several factors will determine whether harmful health effects will occur and what the type and severity of those health effects will be. These factors include the dose (how much), the duration (how long), the route or pathway by which you are exposed (breathing, eating, drinking, or skin contact), the other chemicals to which you are exposed, and your individual characteristics such as age, sex, nutritional status, family traits, life style, and state of health. 1.1 WHAT IS 1,3-BUTADIENE? 1,3-Butadiene is a colorless gas with a mild gasoline-like odor. 1.3-Butadiene is almost always found at low levels in urban air samples, but it breaks down quickly in the air. In sunny weather, half of 1,3-butadiene goes away from the air in about 2 hours. Sunlight is not necessary for the removal of 1,3-butadiene from air, but it helps. In the winter time when the days are short or if it is not sunny, about half of it would still be gone in a few days. Because we do not have enough information, we are not sure exactly what happens to 1,3-butadiene in soil or water. We do not know how often 1.3-butadiene is found in soil or water samples because we do not have reliable methods of looking for it there. If 1,3-butadiene were spilled on water or soil, based on its properties, we expect it to evaporate quickly into the air. We do not expect 1,3-butadiene to collect in plants or fish or to be found in the sediment of rivers and lakes. We also don't expect 1,3-butadiene to be found in soil or underground water sources, but we don't know this for sure. We also don't know how long it takes for 1,3-butadiene to break down in soil or in water because these types of studies have not been done. 0002037141 X J 0002037142 2 1. PUBLIC HEALTH STATEMENT 73 CD Very large amounts of 1,3-butadiene are produced every year from petroleum. 1,3-Butadiene is used to make man-made rubber, which is then used mostly for car and truck tires. It is also used to make other kinds of rubber and plastics. 1,3-Butadiene is also found in small amounts in gasoline. Some plastics or man-made rubbers may have very small amounts of 1,3-butadiene trapped in them. These levels are not expected to be high enough to cause health problems. Small amounts are found in the exhaust of automobiles and trucks at approximately 10 parts in 1 billion parts of air (ppb) and in gasoline vapors at 4 ppb. 1,3-Butadiene is also found in cigarette smoke, and it may also be found in the smoke of wood fires. You will find more information on the chemical properties of 1,3-butadiene in Chapter 3. The uses of 1,3-butadiene are given in Chapter 4. More information on how 1,3-butadiene will behave in the environment is given in Chapter 5. 1.2 HOW MIGHT I BE EXPOSED TO 1,3-BUTADIENE? You can be exposed to 1,3-butadiene by breathing air, drinking water, or eating food contaminated with it. Also, people most likely to be exposed to 1,3-butadiene are workers in the production of rubber, plastics, and resins. 1,3-Butadiene has been found at three hazardous waste sites. It has been detected in gases coming from soil. We do not have enough information to know exactly how people near hazardous waste sites may be exposed to 1,3-butadiene. Because 1,3-butadiene is a gas, you are most likely exposed to it by breathing contaminated air. Large amounts of 1,3-butadiene in the air come from leaks or intentional releases at manufacturing plants. Because it is found in the exhaust of cars and trucks, and in the smoke from wood fires and cigarettes, it is always present at very low levels in the air around cities and towns. The average amount of 1,3-butadiene in the air is 0.3 parts of 1,3-butadiene per billion parts of air (ppb) in cities and suburban areas. These levels are not expected to cause any health problems. The amount of 1,3-butadiene in the air may be much higher near polluted cities or near oil refineries, chemical manufacturing plants, and plastic and rubber factories where this chemical is made or used. The amount in the air can also be very high if 1,3-butadiene is accidentally spilled during shipment from one place to another. 1,3-Butadiene has been measured at very low levels (1-10 ppb) in the plastic or rubber of food containers, but it has not often been found in food samples. These amounts are not expected to cause any health problems. The manufacture of food containers is closely regulated by the Food and Drug Administration (FDA) of the United States. 1,3-Butadiene has been found in drinking water, but we do not know what the concentration was or where it came from. You can find more information on how much 1,3-butadiene is in the environment and how you might be exposed to it in Chapter 5. E tZ Z E M M fl A M 3 1. PUBLIC HEALTH STATEMENT 1.3 HOW CAN 1,3-BUTADIENE ENTER AND LEAVE MY BODY? 1,3-Butadiene can enter your body through your lungs if you breathe air contaminated with it. 1,3-Butadiene may also enter your body through the skin if you come into contact with it, but we do not know how much enters this way. We do not know if 1,3-butadiene is present in ground or surface waters near hazardous wastes sites or what happens to it after you drink water contaminated with this compound. Although 1,3-butadiene has been found at only three NPL waste sites, people at or near these waste sites may be exposed by breathing 1,3-butadiene that evaporates into the air. The amount of 1,3-butadiene that enters the body depends on the amount in the environment and the length of time a person comes into contact with it. Animal studies have shown that the breakdown products of 1,3-butadiene leave the body in the urine and in the air breathed out. We don't know what happens to 1.3- butadiene in the body if it is found in water that people drink. More information on how 1,3-butadiene enters and leaves the body can be found in Chapter 2. 1.4 HOW CAN 1,3-BUTADIENE AFFECT MY HEALTH? Short-term exposure to high levels of 1,3-butadiene causes eye, nose, and throat irritation. Exposure to very high levels could occur during accidental release and could lead to symptoms like drunkenness and unconsciousness, or even to death. However, no such accidental releases have been reported so far. We do not know the exact levels in air that cause these effects in humans. Studies of rubber industry workers suggested possible harmful effects such as more cases of heart diseases, blood diseases, lung diseases, and even cancer from the long-term exposure to low levels of 1,3-butadiene. These rubber industry workers were also exposed to other chemicals along with 1.3-butadiene, so we do not know for sure which chemical (or a combination of them) caused these effects. In addition, the effect of harmful habits like smoking was not considered in the evaluation of health risks of occupational exposure to 1,3-butadiene. 1,3-Butadiene has a gasoline-like odor, which some people can smell at a concentration as low as 1.6 ppm. Skin contact with liquid 1,3-butadiene can cause irritation and frostbite in humans. Laboratory animals that breathed in high levels of 1,3-butadiene for a short time died. Mice that survived exposure to 1,3-butadiene longer than 14 days had damage in the organs that make blood cells and damage to nose tissues. Pregnant mice that breathed in low amounts of 1,3-butadiene had miscarriages. Birth defects were found in offspring of rats and mice exposed to 1,3-butadiene during pregnancy. Rats that breathed in lower levels of 1.3-butadiene for more than 1 year had kidney disease and damaged lungs; some of them died. Mice that breathed in lower levels of 1,3-butadiene for more than 1 year had harmful effects in their reproductive organs and damaged livers. Rats and mice that breathed in small amounts of 1,3-butadiene for a long time period developed cancer in many organs. VRD 0002657144 4 1. PUBLIC HEALTH STATEMENT There is no information on human or animal health effects from eating food or drinking water containing 1,3-butadiene. There is no information on animal health effects from skin contact with 1.3- butadiene. A more complete discussion of the effects of 1,3-butadiene on health can be found in Chapter 2. 1.5 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED TO 1.3-BUTADIENE7 We have no reliable medical test to determine whether you have been exposed to 1,3-butadiene at this time, but scientists are trying to find a way to test blood to see if 1,3-butadiene attaches to certain compounds such as deoxyribonucleic acid (DNA) or proteins that are found in the blood. For further information, please read Chapters 2 and 6. 1.6 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT HUMAN HEALTH? The Environmental Protection Agency (EPA) requires industries to report spills of 1 pound or more of 1,3-butadiene. EPA also intends to add 1.3- butadiene to the list of hazardous air pollutants (EPA 1985b). 1.3- Butadiene levels in the workplace are controlled by the Occupational Safety and Health Administration (OSHA). The previous limit in workplace air was 1,000 ppm, averaged over an 8-hour workday in a 40-hour workweek. However, the National Institute for Occupational Safety and Health (NIOSH) recommended that OSHA consider lowering this limit because 1,3-butadiene has caused cancer in animals. OSHA is in the process of lowering it. 1.7 WHERE CAN I GET MORE INFORMATION? If you have any more questions or concerns not covered here, please contact your state health or environmental department or: Agency for Toxic Substances and Disease Registry Division of Toxicology 1600 Clifton Road, E-29 Atlanta, Georgia 30333 This agency can also provide you with information on the location of the nearest occupational and environmental health clinic. Such clinics specialize in recognizing, evaluating, and treating illnesses that result from exposure to hazardous substances. VRD 0002037145 5 2. HEALTH EFFECTS 2.1 INTRODUCTION The primary purpose of this chapter is to provide public health officials, physicians, toxicologists, and other interested individuals and groups with an overall perspective of the toxicology of 1,3-butadiene and a depiction of significant exposure levels associated with various adverse health effects. It contains descriptions and evaluations of studies and presents levels of significant exposure for 1,3-butadiene based on toxicological studies and epidemiological investigations. 2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE To help public health professionals address the needs of persons living or working near hazardous waste sites, the information in this section is organized first by route of exposure--inhalation, oral, and dermal--and then by health effect--death, systemic, immunological, neurological, developmental, reproductive, genotoxic, and carcinogenic effects. These data are discussed in terms of three exposure periods--acute (less than 15 days), intermediate (15--364 days), and chronic (365 days or more). Levels of significant exposure for each route and duration are presented n tables and illustrated in figures. The points in the figures showing noobserved-adverse-effect levels (NOAELs) or lowest-observed-adverse-effect levels (LOAELs) reflect the actual doses (levels of exposure) used in the studies. LOAELs have been classified into "less serious" or "serious" effects. These distinctions are intended to help the users of the document identify the levels of exposure at which adverse health effects start to appear. They should also help to determine whether or not the effects vary with dose and/or duration, and place into perspective the possible significance of these effects to human health. The significance of the exposure levels shown in the tables and figures may differ depending on the user's perspective. For example, physicians concerned with the interpretation of clinical findings in exposed persons may be interested in levels of exposure associated with "serious" effects. Public health officials and project managers concerned with appropriate actions to take at hazardous waste sites may want information on levels of exposure associated with more subtle effects in humans or animals (LOAEL) or exposure levels below which no adverse effects (NOAEL) have been observed. Estimates of levels posing minimal risk to humans (Minimal Risk Levels, MRLs) may be of interest to health professionals and citizens alike. Levels of exposure associated with the carcinogenic effects of 1,3-butadiene are indicated in Figure 2-1. Because cancer effects could occur at lower exposure levels, the figures also show a range for the upper bound of estimated excess risks, ranging from a risk of one in 10,000 to one in 10,000,000 (10"4 to 10-7), as developed by EPA. VRD 0002837147 7 2. HEALTH EFFECTS values in each species and duration category are recorded in Table 2-1 and plotted in Figure 2-1. 2.2.1.2 Systemic Effects The systemic effects of 1,3-butadiene after inhalation exposure are described below. No studies were located regarding musculoskeletal effects in humans or animals after inhalation exposure to 1,3-butadiene. The highest NOAEL values and all reliable LOAEL values for each systemic effect in each species and duration category are recorded in Table 2-1 and plotted in Figure 2-1. Respiratory Effects. Workers exposed to 1,3-butadiene gas during the manufacture of rubber complained of irritation of the eyes, nasal passages, throat, and lungs (Wilson 1944). In some, coughing, fatigue, and drowsiness developed. All symptoms disappeared on removal from the gas. The exposure levels were not stated in the study. No effects in respiratory tissues in rats, mice, guinea pigs, or dogs were found in intermediate-duration studies (Carpenter et al. 1944; Crouch et al. 1979; NTP 1984). The study of Carpenter et al. (1944) was limited because of poorly described methods and the use of few animals per group. After chronic exposure to 1,250 ppm 1,3-butadiene, an increase in nonneoplastic respiratory changes was found in mice (NTP 1984), including chronic inflammation of the nasal cavity, fibrosis, cartilaginous metaplasia, osseous metaplasia, atrophy of the sensory epithelium, and hyperplasia of the respiratory epithelium (Melnick et al. 1990). No lesions of the nasal cavity were found in the controls. However, lung tumors were found in animals at 6.25, 625, and 1,250 ppm (Melnick et al, 1989; NTP 1984) (see Section 2.2.1.8). Lungs of rats exposed chronically to 8,000 ppm 1,3-butadiene revealed metaplasia (Owen et al. 1987). Cardiovascular Effects. In a retrospective epidemiological study, excessive mortality among middle-aged workers in the rubber Industry was noted for certain types of cardiovascular diseases, mainly chronic rheumatic and arteriosclerotic heart diseases (McMichael et al. 1974). Furthermore, increased mortality for arteriosclerotic heart disease was reported among black males in the rubber industry (Matanoski and Schwartz 1987). This result was confirmed in an update of the original study (Matanoski et al. 1988, 1990). However, the authors noted that the practice of categorizing the individuals of unknown race under whites may have caused a slight inflation of the results. No cardiovascular lesions were found in mice or rats after intermediateduration exposure to 8,000 ppm 1,3-butadiene (Crouch et al. 1979; NTP 1984). J TABLE 2'1. Levels of Significant Exposure to 1.3-Butadiene ~ Inhalation > Key to figure Species Exposure frequency/ duration ACUTE EXPOSURE Death 1 Rat 1 d 4 hr/d 2 Rabbit 1d 23 rnin/d 3 Mouse 2 wk 5 d/wk 6 hr/d 4 Mouse 1d 2 hr/d Neurological 3 Human 1d 6-8 hr/d 6 Rabbit 1d 23 min/d Developmental 7 Rat 10 d 6 hr/d Gd 6-15 8 Mousa Reproductive 10 d Gd 6-15 6 hr/d 9 Mouse 5d 6 hr/d 10 Mouse 5d 6 hr/d INTERMEDIATE EXPOSURE Death 11 Rat 13 wk 5 d/wk (i hr/d System NOAEL (ppm) 8.000 8,000 200 8,000 LOAEL (effect) Less serious (ppm) Serious (ppm) 129,000 <LC50) 250,000 122,000 (LCJ0) 250,000 (anesthesia) 1,000 (wavy ribs) 40 (decreased fetal weight) 6,000 (skeletal abnormalities) 200 (extra ribs) 1,000 (sperm head abnormalities) 200 (dead implantations) Reference Shugaev 1969 Carpenter et al. 1944 NTP 1984 Shugaev 1969 to HEALTH EFFECTS Carpenter et el. 1944 Carpenter et al. 1944 Irvine 1901 Hackett et al, 1967 Hackett et el. 1988a Hackett et al. 1968a Crouch et al. 1979 8tl I e B 00 0 AHA VRD 0002037149 R e fe re n c e 4> O) 50 Cc*l M U 9 2. HEALTH EFFECTS 4t6t ID0 0> 0<0} 0 +> <C 64> Ic) O 0K011 Xu o 00u u * c m oa. ~ 0he 40-> O o o o <s Oo fS (PF"*> S erious ________________________LOAEL ( e f f e c t ) __________________________ (ppm ) Less se rio u s NOAEL ppm >( System E x p o s u re fre q u e n c y / d u ra tio n in <s n o o o o o so O 0J -HJedSo Ck'o s a a e *> uI* Et 0V. Cu C* KUSSCCO 0.--o^. *Ioj, *omJ *n1* KMUUM $:e Cd.Kc *o3 a g SC oo MisXIO'S*Xh0 X* -X-n*c. XJViS.3. ft n 9 Ct (Nj a x m to ti V) 9 CSJ "O X I r> id ie <S ^ X *0 y"> 3 e i <n c X sn Iff 9 s! n~i 19 V. X it 4i 3 0 O S pecies Key to fig u re 8 I TABLE 2-1 (Continued) Key to figure3 Species Exposure fretjuency/ duration System NOAEL (ppm) LOAEL (effect) Less serious (ppm) Serious (ppm) Reference CHRONIC EXPOSURE Death 20 Rat 21 Mouse 22 Mouse Systemic 23 Rat 2* Mouse 25 Mouse Neurological 26 Rat 105-111 wk 5 d/wk 6 hr/d 61 wk 5 d/wk 6 hr/d 65 wk 5 d/wk 6 hr/d 1,000 6.25 8,000 (increased mortality) 625 (increased mortality) 20 (increased mortality) Owen et al. 1987 NTP 198* Melnick et al. 1989, 1990 HEALTH EFFECTS 105-111 wk 5 d/wk 6 hr/d 61 wk 5 d/wk 6 hr/d 65 wk 5 d/wk 6 hr/d Resp Cardio Castro Hemato Hepatic Renal Derm/oc Resp 1.000 8.000 8.000 8.000 8,000 1,000 8.000 Cardio Gastro Hepatic Renal Derm/oc Resp Cardio Gastro Hemato 1,250 1,250 20 20 20 20 8,000 (Increased organ weight, metaplasia) 625 625 625 (endothelial hyperplasia) (epithelial hyperplasia (necrosis) 62.5 62.5 62.5 62.5 (epithelial hyperplasia) (epithelial hyperplasia) (epithelial hyperplasia) (anemia) Owen et al. 1987 8,000 (nephrosis) 1,250 (atrophy of nasal olfactory epithelium) NTP 198* Melnick et al. 1989, 1990 )05-)l) wk 5 d/wk 6 hi-/(I 6, 000 Owen et al. 1987 0S UG0Z000 0 a A * TAM.E 7-1 (Continued) Key to figure8 Species Exposure frequency/ duration System NOAEL (ppm) LOAEL (effect) Less serious (ppm) Serious (ppm) Reference 27 Mouse Reproductive 2B Mouse 29 Mouse Cancer 30 Rat 31 Mouse 32 Mouse 61 wk 5 d/wk 6 hr/d 61 wk 5 d/wk 6 hr/d 65 wk 5 d/wk 6 hr/d 105-111 wk 5 d/wk 6 hr/d 61 wk 5 d/wk 6 hr/d 65 wk 5 d/wk 6 hr/d 1.250 MTP 1984 625 (gonadal atrophy) NTP 1984 6.25 (ovarian atrophy) Melnick et al. 1989, 1990 1.000 (CEL) 625 (CEL) 6.25 CEL Owen at al. 1987 NTP 1904 Melnick et al. 1989. 1990 *The number corresponds to entries in Figure 2-1. Cardio = cardiovascular; CEL " cancer effect level; d * day; Derm/oc = detmal/ocular; Gastro * gastrointestinal; Gd gestation day; llemato * hematological; hr " hour; LCjq * lethal concentration. 50Z kill; LOAEL lowest-observed-adverse-effect level; NOAEL " no-observed-adverse-effect level; ppm * parts per million; Resp * respiratory; wk " week HEALTH EFFECTS ISlLtUBBB QNA I > FIGURE 2-1. Levels of Significant Exposure To 1,3-Butadiene - Inhalation ACUTE (<14 Days) 1.000,000 p 100,000 10,000 1.000 100 10 1* 0.1 0.01 0.001 0.0001 0.00001 0.000001 0.0000001 Jh flhr Om eh As #7, 7f Oh Otni #9m 9nkn Key m Mouse r Rat h Rabtotl LC50 LOAEL. lor serious effects (animats) 3 LOAEL lor less serious effects (animals) O NOAEL (animals) A NOAEL (humans) The number nail to each pdnt corresponds to entries In Tatte 2-1. HEALTH EFFECTS ro zsuiK0fl0 <jhj\ FIGURE 2-1 (Continued) INTERMEDIATE (15-364 Pays) Syslemic ,1 000.000 100.000 10.000 1.000 100 10 1 0.1 0.01 0.001 0.0001 0.00001 0.000001 0.0000001 812mOut Ol4m O'* On*" Ol* Onm 0'<* 0*3' 0* O'* Oum O'* Owm O'* 12m ^tSm Key m Mouse # LO*EL lor serious effects (anhnsh) r O IOAEL ter lass serious effects (animals) O NOAEL (animals) CEl Cancer Eltect level The number nasi id each point corresponds lo entries In Table 2-1. * Ooses represent the lowat! dost lasted par study dial produced a hnnorioenlc response and do noi Imply Iha existence ol a threshold lor Iha cancar and polnl. O'#"* O** 18m l9m health effects ro zsiLwmz* oaa FIGURE 2-1 (Continued) CHRONIC (>365 Days) Systemic ! 1,000.000 100.000 10.000 lOr 3rv Os* 0?3r OTS C>23r #2* 1.000 100 10 1 - _ 0 9?tm Owr 21m . #22111 0" 3m*i 025m 321m OsSm OjVn 3?" 3?Sm 0?5m 3lSm 0?Sm 0,,m ,*"o Or* 0 0?tm Ottm #2Sm 29m aim 32m 0.1 0.01 0.001 0.0001 0.00001 0.000001 o.oooooot ky m Mouse ' LOAEL lor serious sheets (antmels) 3 LOAEL lor less serious elfects (anlmnls) O NOAEl {antmefs) CEL'Cancer Effect Level The number next to each point corresponds to entries In Table 2-1. 10-1 -i Estimated Upper10'S Bound Human 10-* _ Cancer Risk Levels 10-T * Doses represent tie lowest dose tested per Study tint produced a tumericanlc response end do not Imply Vie existence ol a Vireshofd tor the eanear end polnl. HEALTH EFFECTS ro tiUEaefleB aaa 15 2. HEALTH EFFECTS Endothelial hyperplasia in the heart (an early preneoplastic lesion) was observed in mice after 61 weeks of exposure (Melnick et al. 1990; NTF 1984). A high incidence of hemangiosarcomas of the heart was also noted in exposed animals (see Section 2.2.1.8). No exposure-related histopathological cardiac lesions were found in rats exposed chronically to up to 8,000 ppm for 2 years (Owen et al. 1987). Gastrointestinal Effects. No studies were located regarding gastrointestinal effects in humans after inhalation exposure to 1,3-butadiene. No histopathological changes were found after examination of gastrointestinal tract tissues of mice following intermediate-duration exposure (NTP 1984). In a chronic-duration study, high incidences of epithelial hyperplasia (a possible preneoplastic lesion) and carcinoma of the forestomach were found among exposed mice (Melnick et al. 1990; NTP 1984), but no exposure-related nonneoplastic gastrointestinal lesions were found in rats exposed chronically to up to 8,000 ppm (Owen et al. 1987). Hematological Effects. A hematological survey of workers at a styrenebutadiene rubber plant revealed little indication of bone marrow toxicity among the workers (Checkoway and Williams 1982). Styrene and 1,3-butadiene were the most significant chemicals in the atmosphere; benzene and toluene were present in much lower concentrations. A group of eight tank farm workers (workers who fill freight train shipping containers) (mean level exposure of 20 ppm) demonstrated slightly lower levels of red blood cells, hemoglobin, platelets, and neutrophils compared with other workers, but these findings were within the normal range. Other epidemiological studies, however, implicated 1,3-butadiene as the possible cause of hematopoietic malignancies among styrene-butadiene rubber workers (McMichael et al. 1975) at exposure levels that may be lower than 20 ppm. No signs of blood dyscrasias were found among 164 animals (rats, rabbits, guinea pigs, dogs) exposed to concentrations up to 6,700 ppm of 1,3-butadiene for 8 months (Carpenter et al. 1944). The results were supported by a 3-month study, in which no effects on hematological indices were found in rats after exposure to 8,000 ppm of 1,3-butadiene (Crouch et al. 1979). A treatment-related macrocytic-megaloblastic anemia was observed in B6C3F1 and NIH mice exposed to 1,250 ppm 1,3-butadiene for 6-24 weeks (Irons et al. 1986a, 1986b). The bone marrow damage was expressed as reduced numbers of red blood cells, decreased hemoglobin concentration and hematocrit, and increased mean corpuscular volume of circulating erythrocytes. The changes were observed in both strains, independently of the occurrence of murine leukemia viruses in the animals. No such changes were evident after 3 weeks exposure of B6C3F1 mice to the same concentration (Irons et al. 1986a). Decreases in red blood cell counts and hemoglobin concentrations were reported 30 5S S3 ro a c^> --J I--l VRD 0002037156 16 2. HEALTH EFFECTS in male mice after an intermediate duration exposure to 62.5 ppm or more 1,3-butadiene (Melnick et al. 1989, 1990). In contrast to the findings in mice, no effects on hematology and blood chemistry of Sprague-Dawley rats were observed after exposure to 1.000 and 8,000 ppm of 1,3-butadiene for 105-111 weeks (Owen et al. 1987). The hematological effects in mice after chronic exposure consisted of malignancies of the hematopoietic system (Melnick et al. 1989, 1990; NTP 1984) (see Section 2.2.1.8). Hepatic Effects. No studies were located regarding hepatic effects of 1.3- butadiene in humans after Inhalation exposure. No histopathological changes in livers of rats (Crouch et al. 1979) or mice (NTP 1984) were found after intermediate-duration exposure to 1.3- butadiene. The relative liver weights of both sexes of Sprague-Dawley rats were elevated after the chronic exposure to 1,3-butadiene (1,000 and 8,000 ppm); however, this finding was not associated with any pathological changes (Owen et al. 1987). Mice, on the other hand, in addition to the neoplastic changes (see Section 2.2.1.8), had a significant increase in liver necrosis at both exposure levels (625 and 1,250 ppm 1,3-butadiene) (NTP 1984). Renal Effects. No studies were located regarding renal effects in humans after inhalation exposure to 1,3-butadiene. The results of urinalysis in 164 animals, including rats, guinea pigs, rabbits, and dogs were all normal after an 8-month exposure to concentrations up to 6,700 ppm of 1,3-butadiene (Carpenter et al. 1944), but the methods were poorly described. These results were supported, however, in rats after 13 weeks exposure to concentrations up to 8,000 ppm of 1,3-butadiene (Crouch et al. 1979). Furthermore, no renal pathology was found in mice after exposure to 8,000 ppm for 14 weeks or 1,250 ppm for 61 weeks (NTP 1984). Nephrosis was found among male rats after 111 weeks of exposure to 8,000 ppm, but not 1,000 ppm of 1,3-butadiene (Owen et al. 1987). Dermal/Ocular Effects. Two men reported slight irritation of the eyes and difficulty in focusing on instrument scales during 6-7 hours exposure to 2.000 and 4,000 ppm 1,3-butadiene (Carpenter et al. 1944). Ophthalmologic examination of the eyes of dogs and rabbits disclosed no signs of injury during the course of exposure to up to 6,700 ppm 1,3-butadiene for 8 months (Carpenter et al. 1944). After the termination of the experiment, histological examination revealed that the sclera, cornea, and ciliary body were normal. Sections of the optic nerve with adjacent retina showed no myelin sheath degeneration. Although the ophthalmological 0002037157 17 2, HEALTH EFFECTS examination was described in detail, the study was limited by the small number of animals used. No histopathological dermal or ocular changes were found in rats or mice after 13--14 weeks exposure to 8,000 ppm (Crouch et al. 1979; NTP 1984) or in rats after 111 weeks exposure to 8,000 ppm 1,3-butadiene (Owen et al. 1987). 2.2.1.3 Immunological Effects No studies were located regarding immunological effects of 1,3-butadiene in humans after inhalation exposure. After 3-21 weeks of exposure to 1,250 ppm 1,3-butadiene, an increased expression of murine leukemia virus (HuLV) was observed in hematopoietic tissues of B6C3F1 mice, but not in NIH mice (Irons et al. 1987a). Furthermore, altered regulation of the stem cell development in B6C3F1 strain was reported after similar exposure (Leiderman et al. 1986). The significance of these results is discussed in the subsection on cancer in Section 2.4. No severe immunological changes were detected after evaluation of specific humoral and cell-mediated immunity in B6C3F1 mice exposed to 1,250 ppm 1,3-butadiene for 6, 12, or 24 weeks (Thurmond et al. 1986). Suppression of cytotoxic T-lymphocyte generation to mastocytoma cells was observed after 6 weeks, but recovered after 12 weeks of exposure. The histological examination of lymphoid organs showed depressed spleen cellularity after 24 weeks of exposure; this value is recorded as a LOAEL for immunological effects in Table 2-1 and plotted in Figure 2-1. 2.2.1.4 Neurological Effects Inhalation of 1,3-butadiene is mildly narcotic in humans at low concentrations (not otherwise specified) and may result in a feeling of lethargy and drowsiness (Sandmeyer 1981). At very high concentrations, 1,3-butadiene causes narcosis leading to respiratory paralysis and death. The first signs observed in humans are blurred vision, nausea, paresthesia and dryness of the mouth, throat, and nose, followed by fatigue, headache, vertigo, decreased blood pressure and pulse rate, and unconsciousness. Respiratory paralysis is likely to occur only after exposure to high concentrations of 1,3-butadiene such as after spills or leaks. Psychomotor responses of two men inhaling 2,000, 4,000 or 8,000 ppm 1,3-butadiene for 6--8 hours/day on different days were evaluated by Carpenter et al. (1944). At the two higher concentrations, the subjects performed a steadiness test; at the highest concentration, a tapping rate test was also performed. Results after 1,3-butadiene exposure were identical to those obtained before exposure. VRD 000 203715 & 18 2. HEALTH EFFECTS Rabbits exposed to 250,000 ppm of 1,3-butadiene went through all stages of anesthesia to death in the average time of 23 minutes (Carpenter et al. 1944). Less than 2 minutes of exposure was required for loss of motor and labyrinth reflexes. No effects on erythrocyte or brain cholinesterase or on neuromuscular function tests were found in rats exposed to up to 8,000 ppm for 13 weeks (Crouch et al. 1979). In intermediate and chronic exposure studies in mice and rats, no treatment-related histopathological lesions were found in organs and tissues of the nervous system (brain, spinal cord, sciatic nerves) (Crouch et al. 1979; NTP 1984; Owen et al. 1987). Tests for neurological functions were not performed by NTP (1984) and were unreliable as performed by Owen et al. (1987) because mammary tumors interfered with the mobility of rats. The highest NOAEL values and all reliable L0AEL values for neurological effects in each species and duration category are recorded in Table 2-1 and plotted in Figure 2-1. 2.2.1.5 Developmental Effects No studies were located regarding developmental effects in humans after inhalation exposure to 1,3-butadiene. When exposed to concentrations up to 8,000 ppm of 1,3-butadiene during gestation days 6--15, Sprague-Dawley rats showed signs of dose-related maternal and fetal toxicity (Irvine et al. 1981). Depressed body weight gain among dams was observed at all concentrations, and fetal growth was significantly decreased in the 8,000 ppm group. The fetotoxicity of 1,3-butadiene was expressed by a statistically significant increased incidence of skeletal abnormalities (wavy ribs, irregular rib ossification) in the 1,000 ppm group and by major abnormalities (defects of the skull, spine, sternum, long bones, and ribs) in the 8,000 ppm group. In a study in which female outbred SpragueDawley derived rats were exposed to 1,3-butadiene at concentrations up to 1,000 ppm during gestation days 6-15 (Hackett et al. 1987a), some skeletal abnormalities and ossification reductions were found in the fetuses, but were not statistically significant and not considered to be treatment related. In contrast, fetotoxicity expressed as decreased fetal weight was observed in male mice fetuses after exposure of dams during gestation days 6-15 to 40 ppm 1,3-butadiene, and increased incidences of extra ribs and reduced ossification of sternebrae were found in fetuses from groups exposed to 200 ppm and 1,000 ppm, respectively (Hackett et al. 1987b). The highest NOAEL value and all reliable LOAEL values for developmental effects in rats for the acute duration category are recorded in Table 2-1 and plotted in Figure 2-1. VRD 000203715 9- 19 2. HEALTH EFFECTS 2.2.1.6 Reproductive Effects No studies were located regarding reproductive effects in humans after inhalation exposure to 1,3-butadiene. A concentration-related increase in the incidence of sperm-head abnormalities occurred in B6C3F1 mice after exposure to 1,000 and 5,000 ppm of 1.3- butadiene for 6 hours/day for 5 days (Hackett et al. 1988a). Dominant lethality in CD-I mice was also observed during the first 2 postexposure weeks after the males were exposed to 200, 1,000 but not 5,000 ppm (Hackett et al. 1988b). The study was considered to be inconclusive because of the lack of dose response. In animals exposed to 6,700 ppm or less 1,3-butadiene, no impairment of fertility was noted when groups of male and female rats, rabbits, or guinea pigs were housed together and allowed to mate freely (Carpenter et al. 1944). In intermediate duration studies, no histopathological evidence of treatmentrelated effects in reproductive organs of rats (Crouch et al. 1979) or mice (NTP 1984) was found, but reproductive function was not assessed in these studies. In a chronic study, exposure of mice to 6.25 ppm or more of 1,3-butadiene resulted in an increased incidence of ovarian atrophy in females (Melnick et al. 1989, 1990), while a corresponding increase in testicular atrophy was observed in males only after exposure to 625 ppm (Melnick et al. 1989, 1990; NTP 1984). The data indicated high susceptibility of female mice to 1.3- butadiene-induced effects in reproductive organs. Malignant tumors in reproductive tissues were found after chronic exposure in rats, but reproductive functions were not evaluated (Owen et al. 1987). All reliable LOAEL values for effects in the reproductive system in mice in each duration category are recorded in Table 2-1 and plotted in Figure 2-1. 2.2.1.7 Genotoxic Effects No significant differences in cytogenetic analysis (chromosome aberrations and sister chromatid exchanges in peripheral lymphocytes) were found between a group of 30 styrene-butadiene rubber workers and a group of matched controls (Zhou et al, 1986). The influence of sex, age, or smoking habits was evaluated in the study. However, the exact exposure levels to 1.3-butadiene were not measured. Generally, no genotoxic effects were found In bone marrow of rats exposed by inhalation to 1,3-butadiene (Choy et al. 1986; Cunningham et al. 1986). B6C3F1 mice were exposed to 1,3-butadiene at concentrations up to 10,000 ppm for 6 hours/day for 2 days (Choy et al. 1986). A statistically significant dose-related increase in micronucleus induction was observed in mice beginning at 100 ppm. The frequency of micronucleated polychromatic erythrocytes was also significantly increased in B6C3F1 mice exposed 6 hours/day, 5 days/week VRD 0002031168 20 2. HEALTH EFFECTS for 13 weeks to concentrations of 62.5 and 625 ppm of 1,3-butadiene (Jauhar et al. 1988). In B6C3F1 mice exposed to 6.25, 62.5, and 625 ppm of 1.3- butadiene for 6 h.ours/day for 10 days, the most sensitive indicator of genotoxic damage was the frequency of sister chromatid exchanges (statistically significant at 6.25 ppm), followed by micronucleated polychromatic erythrocyte levels (statistically significant at 62.5 ppm), and then by chromosomal aberration frequencies (statistically significant at 625 ppm) (Tice et al. 1987). A statistically significant increase in sister chromatid exchange was also observed in mice starting at 100 ppm of 1.3- butadiene, with a four-fold increase over control levels evident at 10.000 ppm (exposure 6 hours/day for 2 days) (Cunningham et al. 1986). In B6C3F1 and NIH Swiss mice, comparable increases in the frequency of chromosomal aberrations were observed following exposure to 1,250 ppm of 1.3- butadiene for 6 hours (Irons et al. 1987b). These results indicate that 1.3- butadiene-treatment in vivo produces significant increases in chromatid aberrations in both strains. In a dominant lethal study in which male CD-I mice were exposed to 1.3- butadiene for 5 days and mated to nonexposed females, an increased number of dead implantations per pregnancy occurred at 200 and 1,000 ppm, but not at 5.000 ppm during the first 2 weeks postexposure (Hackett et al. 1988a). These results were considered to be inconclusive because of the lack of a strict dose-response relationship. Other genotoxicity studies are discussed in Section 2.4. 2.2.1.8 Cancer Epidemiological retrospective studies of mortality among workers in the rubber industry were conducted by several investigators (Case and Hosker 1954; Fox et al. 1974; Matanoski and Schwartz 1987; Matanoski et al. 1982, 1988, 1990; McMichael et al, 1974, 1975, 1976; Meinhardt et al. 1982). Occupational exposure in styrene-butadiene rubber plants was linked to increased incidences in respiratory, bladder, stomach, and lymphato-hematopoietic cancers. Because workers were exposed to mixtures of various chemicals, the contribution of 1,3-butadiene exposure to the development of these effects was unclear. Therefore, an attempt has been made to link the effects to specific exposures. When the workers were grouped according to a work area and a job longest held, production workers had increased Standard Mortality Ratios (SMR) for heraatolyraphopoietic neoplasms (SMR was 230 for other lymphatic neoplasms in whites; SMRs were 532 for lymphosarcoma, 656 for leukemia, and 484 for other lymphatic neoplasms in blacks) and maintenance workers had increased SMRs for digestive cancers (SMRs were 144 for esophageal and 166 for stomach cancer in whites) (Matanoski et al. 1990). The Matanoski et al. (1982, 1988, 1990) studies were, however, confounded by assuming the individuals of unknown race (152 of the total) to be white. This approach may have caused a slight inflation of results on racial distribution of mortality from cancers in the cohort. A nested case-control study for hemato-lymphopoietic cancers was performed in VRD 0002837161 21 2. HEALTH EFFECTS one of the original cohorts of styrene-butadiene rubber workers (Matanoski et al. 1989b). The leukemia cases were associated with exposure to 1,3-butadiene (odds ratio-9.4). No such an association was found for exposure to styrene. The results were supported by a study in a 1,3-butadiene-monomer manufacturing plant (Downs et al. 1987). A higher mortality rate for lymphosarcoma and reticulum cell sarcoma (SMR-235) was reported in the cohort. Observed deaths from cancer of gastrointestinal, respiratory, urinary, and skeletal systems were also statistically evaluated in this cohort and compared with the expected numbers. No increase in mortality was reported for these categories. Similar results were reported in an update of the study (SMR--229 for lymphosarcoma) (Divine 1990). However, almost half of the cohort worked less than 5 years in the industry and the workers also had an occupational history of working in other chemical industries. The lack of historic exposure data to 1,3-butadiene and, as mentioned above, possible exposure to other chemicals are the main confounding factors of epidemiological studies in 1,3-butadiene exposed workers. In addition, though adjustments for age, calendar time, and race were done in most studies, the adjustment for smoking was lacking. Lymphocytic lymphomas were found in B6C3F1 mice exposed to 200 ppm 1.3- butadiene for 40 weeks and observed up to 104 weeks (Melnick et al. 1990). Further experiments with various intermediate-durations and various levels of exposure indicated that tumor types other than lymphocytic lymphoma had a better chance to develop with longer survival of the animals. When B6C3F1 mice were exposed for 61 weeks to 625 or 1,250 ppm 1.3- butadiene, multiple-site carcinomas developed (NTP 1984). The most common were heraangiosarcoraa of the heart, malignant lymphoma, alveolar/bronchiolar adenoma and carcinoma, papilloma and carcinoma of the stomach, hepatocellular adenoma or carcinoma, and mammary gland and ovary carcinomas and nonmalignant granulosa cell tumors. When the chronic exposure study in mice was repeated, lymphocytic lymphomas were the major cause of death in groups exposed to 625 ppm 1,3-butadiene (Melnick et al. 1989, 1990). An increased incidence of hemangiosarcoma of the heart was found in males exposed to 62.5 ppm and higher. Furthermore, the incidence of alveolar-bronchiolar neoplasms was increased in males exposed to 62.5 ppm 1,3-butadiene and in females exposed to doses as low as 6.25 ppm (Melnick et al. 1989). Multiple carcinomas occurred in rats after chronic exposure to 1,000 ppm and 8,000 ppm 1,3-butadiene for 105/111 weeks (Owen et al. 1987). Significantly increased incidences of Leydig cell adenoma, pancreatic exocrine adenoma, uterine sarcoma, mammary tumors, Zymbal gland carcinoma, and thyroid follicular cell tumors were observed in the higher concentration group. The cancer effect levels (CELs) are recorded in Table 2-1 and plotted in Figure 2-1. 19 tm 0 0 0 22 2. HEALTH EFFECTS 30 O Using the tumor data from male and female mice in the NTP (1984) study, EPA derived a unit risk for inhalation exposure of 6x10"* ppb (IRIS 1991) . This unit risk corresponds to upper bound individual lifetime cancer risks at 10'* to 10"7 risk levels of 2x10"* to 2xl0"7 ppm, which are plotted In Figure 2-1. The unit risk should not be used if the air concentration exceeds 7.2 ppb, since above this concentration, the slope faccor may differ from that stated (IRIS 1991). The EPA derivation does not take into consideration the more recent study by Melnick et al. (1989, 1990) because the data were not available at the time of the qj* derivation. Furthermore, the latest data regarding species differences in 1,3-butadiene toxicokinetics between rodents and primates indicated that mice may be more susceptible to 1,3-butadiene-Induced effects (Dahl et al. 1990; Sun et al. 1989a). 2.2.2 Oral Exposure No studies were located regarding the following health effects in humans or animals after oral exposure to 1,3-butadiene. 2.2.2.1 2.2.2.2 2.2.2.3 2.2.2.4 2.2.2.5 2.2.2.6 2.2.2.7 Death Systemic Effects Immunological Effects Neurological Effects Developmental Effects Reproductive Effects Genotoxic Effects Genotoxicity studies are discussed in Section 2.4. 2.2.2.8 Cancer No studies were located regarding cancer in humans or animals after oral exposure to 1,3-butadiene. 2.2.3 Dermal Exposure Dermal contact with liquid 1,3-butadiene causes a sensation of cold followed by a sensation of burning, which is the result of rapid evaporation; this may cause frostbite. High gas concentrations may cause mild skin irritation as well (MCA 1974). No other studies were located regarding the following health effects in humans or animals after dermal exposure to 1,3-butadiene. 2.2.3.1 2.2.3.2 2.2.3.3 2.2.3.4 Death Systemic Effects Immunological Effects Neurological Effects VRD 0002037163 23 2. HEALTH EFFECTS 2.2.3.5 2.2.3.6 2.2.3.7 Developmental Effects Reproductive Effects Genotoxic Effects Genotoxicity studies are discussed in Section 2.4 2.2.3.8 Cancer No studies were located regarding cancer in humans or animals after dermal exposure to 1,3-butadiene. 2.3 TOXICOKINETICS 2.3.1 Absorption 2.3.1.1 Inhalation Exposure No studies were located regarding absorption of 1,3-butadiene in humans after inhalation exposure. The distribution coefficient for 1,3-butadiene between rabbit blood and air was 0.603 In vitro and 0.654 in vivo. suggesting simple passive diffusion of the gas from the alveoli to the blood (Carpenter et al. 1944). After 9 minutes exposure of rabbits to 250,000 ppm, the concentration of 1,3-butadiene was 0.26 mg/mL in the femoral artery and 0.18 mg/mL in the femoral vein. Pulmonary absorption, therefore, appears to be rapid. Distribution studies in rats and mice following inhalation exposure to 1,3-butadiene indicate that it is absorbed from the lungs in these species as well (see Section 2.3,2.1). When Macaca fascicularis monkeys were exposed to radioactively labeled 1,3-butadiene, the uptake was calculated as 16.40 /imol/hour/10 ppm of inhaled and 3.20 jmol/hour/10 ppm of retained 1,3-butadiene (Dahl et al. 1990). 2.3.1.2 Oral Exposure No studies were located regarding absorption in humans or animals after oral exposure to 1,3-butadiene. 2.3.1.3 Dermal Exposure No studies were located regarding absorption in humans or animals after dermal exposure to 1,3-butadiene. VRD 0007037164 24 2. HEALTH EFFECTS 2.3.2 Distribution 2.3.2.1 Inhalation Exposure No studies were located regarding distribution in humans after inhalation exposure to 1,3-butadiene. The distribution of 1,3-butadiene in several tissues in rats was measured following a 1-hour inhalation exposure to 129,000 ppm (Shugaev 1969). There was a high concentration of 1,3-butadiene in perinephric fat with lower levels in the brain, liver, septum, and kidney. These levels decreased with time; at 90 minutes following inhalation exposure, only trace levels of 1,3-butadiene could be found. Species differences in the distribution of inhaled 1,3-butadiene were studied in Sprague-Dawley rats and B6C3F1 mice (Bond et al. 1986, 1987). The tissues from both species contained high concentrations of l4C-1,3-butadiene derived radioactivity 1 hour postexposure. The mouse tissues contained up to seven times more of 1,3-butadiene and its metabolites in their tissues as compared to rats, while up to five times more was detected in their blood. 2.3.2.2 Oral Exposure No studies were located regarding distribution in humans or animals after oral exposure to 1,3-butadiene. 2.3.2.3 Dermal Exposure No studies were located regarding distribution in humans or animals after dermal exposure to 1,3-butadiene. 2.3.3 Metabolism The amount of 1,2-epoxybutene-3 formed in postmitochondrial preparations from human liver was proportional to the monooxygenase activity, but lower when compared with the amount formed in postmitochondrial preparations from livers of rats and mice (Schmidt and Loeser 1985, 1986). These species differences in the metabolism of 1,3-butadiene to the epoxide suggest differences between humans and rodents in the expression of 1,3-butadiene toxicity (see Section 2.4). The metabolism of 1,3-butadiene was studied by Malvoisin et al. (1979) in rat liver microsoraes. One of the major metabolites of 1,3-butadiene was found to be 1,2-epoxybutene-3. Hepatic microsomal metabolism was further investigated (Malvoisin and Roberfroid 1982), and the hypothetical metabolic pathway shown in Figure 2-2 was proposed. 1,3-Butadiene was metabolized to 1,2-epoxybutene-3, which was then transformed into 3-butene-l,2-diol by microsomal epoxide hydrolase. In the metabolism of 1,2-epoxybutene-3 in 25 2. HEALTH EFFECTS FIGURE 2-2. Microsomal Metabolic Pathway of 1,3-Butadiene In Rats* ch2ch-chch2 1,3-butadiene , I NAOPH, Oj, microsomes Yo /\ CH_2 CH CH - CH 2,, 1,2-epoxybutene-3 CH_-CH-CH-CH, !I OH OH 3-buten-1.2 did ^ NADPH, 02, microsomes CHg* CH - CH - CH. \/ i i O OH OH 3,4-epo*y*1.2-butone diol (both stereoisomers produced) O DL-diepoxybutane (both stereoisomers produced) Adapted from Malvolsin and Roberfroid 1962 S 9U tl00fl vs C3 0002037166 26 2. HEALTH EFFECTS so o microsomes, two stereoisomers of DL-diepoxybutane, and two stereoisomers of 3,4-epoxy-1,2-butanediol were detected as further metabolites. The participation of cytochrome P-450 in the metabolism of 1,3-butadiene was suggested on the basis of experimental data (Bolt et al. 1983). The amount of epoxide formed in the rat liver microsomes was dependent on incubation time, microsomal protein, and substrate concentration. Species differences in the formation of 1,2-epoxybutene-3 from 1,3-butadiene were first studied by Schmidt and Loeser (1985, 1986). A high capability of mouse liver and especially lung postmitochondrial fractions to produce 1,2-epoxybutene-3 after incubation with 1,3-butadiene was demonstrated. In comparison, rat liver and lung produced significantly less 1,2-epoxybutene-3. Pharmacokinetic analysis revealed species differences between rats and mice after inhalation exposure to 1,2-epoxybutene-3 (Kreiling et al. 1987; Laib et al. 1990). A limited rate of 1,2-epoxybutene-3 detoxification and its subsequent accumulation was observed in mice at 500 ppm exposure, but not in rats at exposures up to 5,000 ppm. This may partially account for the differing levels of toxicity and carcinogenicity between rats and mice long-term studies. Monkey postmitochondrial liver preparations catalyzed only a slow formation of the epoxide; no epoxide was detected with lung preparations. Species differences in the ability of 1,3-butadiene to bind covalently to nucleoproteins and DNA from the liver were found in B6C3F1 mice and Wistar rats exposed to UC-1,3-butadiene (Kreiling et al. 1986a). In correspondence with the higher metabolic rate of 1,3-butadiene in mice, the formation rate of reactive protein-binding metabolites was about twice as high in this' species as noted in rats. Other experiments demonstrated protein-DNA and DNA-DNA crosslinks in the liver tissues in B6C3F1 mice, but not in Wistar rats following exposure to 14C-1,3-butadiene (Jellito et al. 1989). The crosslinking was due to the reaction of 1,3-butadiene metabolites (1,2-epoxybutene-3 and diepoxybutane) with guanine. Further differences between mouse and rat metabolism were observed in the ability of 1,3-butadiene to deplete nonprotein sulfhydryl (NPSH) (Deutschmann and Laib 1989; Kreiling et al. 1988). The depletion of NPSH content was greater in mice than in rats after 1,3-butadiene exposure, suggesting that detoxification of active metabolites proceeds mainly via glutathione-S-transferase mediated pathways in mice. Further differences were noted between 1,3-butadiene metabolism in rodents and in monkeys (Dahl et al. 1990; Sun et al. 1989a). At low exposure levels, blood levels of toxic metabolites were lower in monkeys than in rodents. The difference was not so great at higher 1,3-butadiene exposures (Sun et al. 1989a). Similar exposures to lower 1,3-butadiene levels, however, resulted in blood concentrations of total 1,3-butadiene metabolites in monkeys that were about 5-50 times lower than in mice and about 4-14 times lower than in rats (Dahl et al. 1991). The results indicated possible lower susceptibility to toxic effects of low levels of 1,3-butadiene in monkeys. 27 2. HEALTH EFFECTS 2.3.4 Excretion 2.3.4.1 Inhalation Exposure . No studies were located regarding the excretion of 1,3-butadiene in humans following inhalation exposure to 1,3-butadiene. In rats exposed to 1,3-butadiene, 1,2-epoxybutene-3 and acetone were exhaled as suspected metabolites of the administered compound (Bolt et al. 1983). The pharmacokinetic profile of inhaled 1,3-butadiene was studied in mice (Kreiling et al. 1986b) and in rats (Bolt et al. 1984; Filser and Bolt 1984). Following exposure of mice and rats to 14C-1,3-butadiene, the elimination of radioactivity was rapid, and 77X-99X of the initial tissue amount was eliminated with half-times of between 2 and 10 hours (Bond et al. 1987). At concentrajtions of approximately 1,000 ppm or less, the elimination of 1,3-butadiene followed first-order kinetics in both species. The firstorder metabolic clearance of inhaled 1,3-butadiene per kg body weight was 4,500 mL/hour for rats (Laib et al. 1988) and 7,300 mL/hour for mice (Kreiling et ai. 1986b). The maximal metabolic elimination rate was calculated as 220 /imol/hour/kg for rats (Laib et al. 1988) and 400 /imol/hour/kg for mice (Kreiling et al. 1986b). With increasing concentrations of 14C-1,3-butadiene, exhalation of radiolabeled carbon was a major pathway for elimination of 14C in mice and rats (Bond et al. 1986). About 2X of the total inhaled amount of 1,3-butadiene was excreted as its metabolites in Cynomolgus monkeys (Sun et al. 1989a). Carbon dioxide was the major exhalatory product at low exposure levels, while epoxy-metabolites were exhaled at higher levels. Urinary excretion of total metabolites was not influenced by exposure levels. In Macaca fascicularis monkeys, about 39X of metabolites was eliminated in the urine, 0.8X in feces, and 56X was exhaled as carbon dioxide during the first 70 hours postexposure (Dahl et al. 1990). 2.3.4.2 Oral Exposure No studies were located regarding excretion in humans or animals after oral exposure to 1,3-butadiene. 2.3.4.3 Dermal Exposure No studies were located regarding excretion in humans or animals after dermal exposure to 1,3-butadiene. 2.4 RELEVANCE TO PUBLIC HEALTH Epidemiological studies have suggested a possible risk of harmful effects associated with occupational exposure to 1,3-butadiene by finding a higher incidence of cardiovascular and hematopoietic diseases, respiratory diseases, and cancer among exposed workers, but exposures were not to 1,3-butadiene 00020 B71 6 7 S*3 VRD 0002037168 28 2. HEALTH EFFECTS exclusively. Narcosis and death from respiratory paralysis may occur in humans and animals after inhalation exposure to very high concentrations of 1,3-butadiene. In animals, effects include increased mortality, anemia, respiratory lesions', liver necrosis, nephrosis, and cancer. Fetotoxic and reproductive effects have been observed in mice after exposure to 1,3-butadiene. Data regarding exposure levels and their correlation vith observed effects from studies in humans exposed by the Inhalation route were insufficient to derive MRL values. The toxicity of 1,3-butadiene has been studied in animals by the inhalation route. A few acute-duration toxicity studies vere conducted that did not, however, evaluate many of the systemic end points (Carpenter et al. 1984; Shugaev 1969). Developmental effects were observed in the offspring of rats and mice exposed to 1,3-butadiene during gestation (Hackett et al. 1987b; Irvine 1981). Fetotoxicity in mice was observed in the lowest 1,3-butadiene concentration tested from all acute studies. Therefore, no acute-duration inhalation MRL was derived. Intermediate-duration studies showed that 1,3-butadiene induces anemia in mice at low exposure levels by interfering with normal bone marrow development (Irons et al. 1986a). The changes resembled those found in human preleukemic syndrome (Biemer 1983). Toxicity studies In mice provided evidence that the mouse is highly susceptible to 1,3-butadiene-induced effects. Toxicokinetic studies indicated that the susceptibility may be due to the differences in metabolism of 1,3-butadiene between mice and other species (Deutschmann and Lalb 1989; Jellito et al. 1989; Krelllng et al. 1986a, 1987, 1988; Schmidt and Loeser 1985, 1986). These included variations in the formation rate of toxic metabolites, in the extent of covalent binding of metabolites to proteins and DNA, and in the ability to deplete nonprotein sulfhydryl content. It was demonstrated that blood levels of toxic metabolites were much lower in 1.3-butadiene-exposed monkeys than in mice (Dahl et al. 1990; Sun et al. 1989a). The difference was not, however, so distinct at higher exposure levels. Humans are more likely to be exposed to low 1,3-butadiene concentrations at which the greatest interspecies differences were observed. Therefore, the high susceptibility of the mouse to toxic effects of low 1.3-butadiene levels makes its use in the derivation of health hazard risk assessment for humans questionable. The only other species tested in inhalation studies was the rat (Crouch et al. 1979). However, the study did not identify target organs. MRL was derived. Therefore, no intermediate-duration inhalation Chronic-duration studies were conducted in rats (Owen et al. 1987) and In mice (NTP 1984). The study in mice was repeated with lower exposure levels (Melnick et al. 1989, 1990). Multiple-site neoplasms developed in exposed animals of both species. The low exposure study in mice provided NOAEL and LOAEL levels for hematological, respiratory, cardiovascular, and VRD 0002037169^ 29 2. HEALTH EFFECTS gastrointestinal effects. However, increased mortality and reproductive effects were reported in the study at the same exposure level as these systemic NOAELs. Therefore, the results were not suitable for the derivation of a chronic-duration inhalation MRL. No studies were located regarding effects in humans or animals after oral exposure. Therefore, no acute-, intermediate-, and chronic-duration oral MRLs could be derived. Acute-, intermediate-, and chronic-duration dermal MRLs were not derived for 1,3-butadiene due to the lack of data and an appropriate methodology for the development of dermal MRLs. Death. No case reports were located regarding acute lethality of 1,3-butadiene in humans. Evidence of an anesthetic effect of 1,3-butadiene leading to death in animals after very high exposures (greater than 120,000 ppm) was given by Carpenter et al. (1944) and Shugaev (1969). Retrospective mortality studies among workers in the rubber industry have revealed an increased incidence of death from cancer, cardiovascular diseases, and diabetes (Case and Hoskar 1954; Fox et al. 1974; Matanoski and Schwartz 1987; Matanoski et al. 1982; McMichael et al. 1974, 1975, 1976; Meinhardt et al. 1982). These findings are supported by chronic exposure studies on mice (Melnick et al. 1989, 1990; NTP 1984) and rats (Owen et al. 1987) where deaths from cancer were increased among exposed animals. It is also not known whether long-term exposure of humans to low levels of 1,3-butadiene at waste sites or in the environment would lead to diseases that could shorten the lifespan. Systemic Effects Respiratory Effects. The data regarding respiratory effects due to acute exposure to 1,3-butadiene in humans are limited to reports on irritation of respiratory passages after inhalation exposure (Wilson 1944). The irritation might cause even more serious health problems with chronic exposure. The findings of nonneoplastic changes in the nasal cavity in mice after chronic exposure to 1,3-butadiene (NTP 1984) support these data. Cardiovascular Effects. The only cardiovascular effects found in humans were those reported by McMichael et al. (1974) regarding excessive deaths from arteriosclerotic and chronic rheumatic heart disease. Endothelial hyperplasia of the heart was found in mice after chronic exposure (Melnick et al. 1990). The potential for cardiovascular effects in humans exposed to 1,3-butadiene at or near hazardous waste sites is not known. Hematological Effects. Slightly lower levels of red blood cells, hemoglobin, platelets, and neutrophils among tank car workers (workers who fill freight train shipping containers) as compared to other workers in the VRD 0002037170 30 2. HEALTH EFFECTS rubber industry were reported by Checkoway and Williams (1982). These results correspond to results observed in exposed mice (Irons et al. 1986a; Melnick et al. 1989, 1990). 1,3-Butadiene treatment-related changes during intermediateduration inhalation exposure included a decrease in circulating erythrocytes, total hemoglobin, hematocrit and a leukopenia, due to a decrease in segmented neutrophils. However, no effects on hematology or blood chemistry of rats were found during a chronic exposure study (Owen et al. 1987). Because hematological effects have been observed in animals after inhalation exposure to 1,3-butadiene and may occur in humans exposed occupationally, hematological effects in people who live at or near hazardous waste sites containing 1,3-butadiene may be possible. Hepatic Effects. No reports were located regarding hepatic effects of 1,3-butadiene in humans. The only adverse effect of 1,3-butadiene in animals, other than cancer, was reported by NTP (1984) in mice, in which chronic inhalation exposure resulted in a higher incidence of liver necrosis. No such changes were found after chronic exposure in rats (Owen et al. 1987). The metabolism via liver microsomes is of great importance in detoxification of 1,3-butadiene in animals (Bolt et al. 1983; Halvoisin et al. 1979). One of the major metabolites of 1,3-butadiene in the liver was 1.2-epoxybutene-3 (Halvoisin and Roberfroid 1982), which was subsequently transformed into 3-butene-1,2-diol by microsomal epoxide hydrolase. The metabolites were mutagenic in in vitro tests (De Meester et al. 1988). The differences in the formation of 1,2-epoxybutene-3 in the postmitochondrial fractions of mice and rats were examined by Schmidt and Loeser (1985, 1986). A higher rate of production of 1,2-epoxybutene-3 was found in mice than rats. i In addition to the higher production rate of 1,2-epoxybutene-3 from 1.3-butadiene, accumulation of the reactive epoxide intermediates, the low capacity for further metabolism, and their detoxification mainly via glutathione-S-transferase-mediated pathways are responsible for the drastic depletion of hepatic NPSH contents in mice (Bond et al. 1988; Deutschmann and Laib 1989; Kreiling et al. 1988). These results partially explain the differing levels of toxicity and carcinogenicity in long-term studies found between mice and rats. Human and monkey postmitochondrial liver fractions catalyzed only a slow formation of the epoxide, and with lung fractions, no epoxide was detected (Schmidt and Loeser 1985, 1986), suggesting that different metabolic rates operate in primates than in rodents. Therefore, the relevance to humans of the liver necrosis observed in mice is not clear. Renal Effects. No studies were located regarding renal effects of 1.3-butadiene in humans. No effects were reported in rats, guinea pigs, rabbits, dogs (Carpenter et al. 1944), rats (Crouch et al. 1979), or mice (NTP 1984) except for the more frequent occurrence of nephrosis in male rats after chronic inhalation exposure to 8,000 ppm 1,3-butadiene (Owen et al. 1987). The relevance of this information to humans is unclear. VRO 0001037171 31 2. HEALTH EFFECTS Immunological Effects. No data were located regarding immunological effects in humans. The effect of 1,3-butadiene exposure on the immune system of mice was investigated by Thurmond et al.(1986), who found a reversible suppression of cytotoxic T-lymphocyte generation to mastocytoma cells and a depression of spleen cellularity. The regulation of stem cell development was altered in B6C3F1 mice after intermediate duration inhalation exposure to 1,3-butadiene (Leiderman et al. 1986). The changes in proliferation and differentiation of hematopoietic cells were similar to those usually preceding the onset of the expression of lymphoma in B6C3F1 mice after chronic exposure to 1,3-butadiene (NTP 1984) (see discussion of Cancer in Section 2.4). No information was found regarding immunological effects and lymphoma in humans after exposure to 1,3-butadiene. However, based upon these studies in laboratory animals where stem cell development was affected, it would be prudent to consider that potentially adverse immunological effects from exposure to 1,3-butadiene could occur in humans. Neurological Effects. Inhalation of high concentrations of 1,3-butadiene is narcotic in humans (Sandmeyer et al. 1981) and animals (Carpenter et al. 1944) and can lead to death from respiratory paralysis (Carpenter et al. 1944; Shugaev 1969). Although the exact concentration leading to narcosis in humans is not known, exposure to 250,000 ppm produced anesthesia in rabbits. Nausea, dryness of the mouth and nose, headache, and decreased blood pressure and julse rate are the first signs observed in humans (Sandmeyer 1981) . These data become relevant for humans only during exposure following industrial accidents resulting in significant leaks or spills of 1,3-butadiene. Developmental Effects. No data were available regarding developmental effects of 1,3-butadiene in humans. Fetotoxic effects (skeletal abnormalities and lens opacity) of 1,3-butadiene exposure were observed in rats (Irvine et al. 1981) and in mice (Hackett et al. 1987) after 1,3-butadiene treatment of pregnant rats during days 6-15 of gestation. Based upon these experimental data in laboratory animals, it would be prudent to consider the potential for adverse health effects from exposure to 1,3-butadiene in humans. The low molecular weight and high lipid solubility of 1,3-butadiene suggest that it may cross the placenta. Reproductive Effects. No studies were located regarding reproductive effects in humans after exposure to 1,3-butadiene. Increased incidence of gonadal atrophy in mice occurred after chronic inhalation exposure to 1,3-butadiene (Melnick et al. 1989, 1990; NTP 1984). Inhalation exposure of male mice to 1,3-butadiene resulted in dominant lethal mutations and sperm head abnormalities (Hackett et al. 1988a, 1988b). Laboratory investigations in animals suggest that 1,3-butadiene affects the more mature cells of the reproductive system. Based upon this information in laboratory animals, the potential for human reproductive effects upon exposure to 1,3-butadiene should be considered. VRD 0002037172 32 2. HEALTH EFFECTS Genotoxic Effects. 1,3-Butadiene has been tested for genotoxicity in a number of in vitro and in vivo studies (Tables 2-2 and 2-3). Positive results have been found in the reverse mutation assay in Salmonella typhimurium TA1530 and TA1535 in the absence or in the presence of metabolic activation system (De Meester et al. 1978). However, the interpretation of these results was confounded by the fact that the Petri dishes not containing S-9 mix were contaminated by volatile active metabolites (De Meester et al. 1988). It was concluded that S-9 mix was necessary to activate 1,3-butadiene into mutagen(s). TA1530 was the most sensitive strain, but 1,3-butadiene mutagenicity was detectable only with metabolic activation in the subsequent study (De Meester et al. 1980). No significant mutagenic effect on S. typhimurium strain TA100 with metabolic activation was observed (Victorin and Stahlberg 1988). A weak genotoxic activity was detected in strain TA1535 with rat S-9 (Arce et al. 1989). On the basis of these data, 1,3-butadiene appears to require metabolic activation to produce genotoxicity. Several recent studies dealt with the mutagenic effect of 1,3-butadiene in vivo. Details of the in vivo studies were discussed In Section 2.2.1.7. A significant dose-related increase in induction of micronuclei was found in mice, but not rats, after intermediate-duration exposure to up to 625 ppm 1,3-butadiene (Jauhar et al. 1988). Also, an increase in the frequency of chromosomal aberrations and sister chromatid exchanges was found in mice (Cunningham et al. 1986; Sharief et al. 1986; Tice et al. 1987). No genotoxic effects were found in rats exposed by inhalation to 1,3-butadiene (Cunningham et al. 1986), as demonstrated by using cytogenetic analysis of their bone marrow. Although cytogenetic monitoring of 1,3-butadiene rubber workers for chromosomal aberrations revealed no significant differences between exposed and control groups (Zhou et al. 1986), 1,3-butadiene is clearly genotoxic in mice. As discussed in Section 2.3.3, species differences exist in the metabolism of 1,3-butadiene, and data suggest that humans may metabolize this compound at different metabolic rates than do rodents. If the genotoxic and clastogenic response of 1,3-butadiene requires activation to an active metabolite that is formed more slowly or deactivated more rapidly in humans than in rats and mice, the genotoxicity observed in animals may only be observed after much higher exposures in humans. The data in humans are too limited, however, to rule out the possibility of a genotoxic potential in humans exposed to 1,3-butadiene. Cancer. An increased incidence of bronchial carcinoma was reported in rubber industry workers (Fox et al. 1974). Although information on smoking was not available in the cohort, no excesses were found in other smokingrelated diseases. However, the possible influence of smoking, occupational coexposure to other chemicals, and/or urban effects could not be ruled out in the study. 33 2. HEALTH EFFECTS HB JC d03l tVi V) ^ 0r-)l so SJ S3 S3 1*0 S3 TABU! 7.-7.. G *r>ot.oxicity o f 1 ,3 -B u tiid ie n e In V i t r o UE fj -- -.-J TABLE 2-3. Gcnotnxieity of 1.3-Butadlone In Vivo Species (test system) End point Results Reference Mansnelian cells: B6C3F1 mice (Inhalation) Sprague-Dawley rats (inhalation) Bone marrow; Dose*dependent Increase in SCEs B6C3F1 mice (Inhalation) Bone marrow; Increase in CA, SCEs, AGT and depression of MI Macrocytic-megaloblastic anemia Bone marrow: *41 increase In proliferative index Swiss mice (inhalation) Macrocytic-megaloblastic anemia 6'FoId increase in circulating micronuclei Bone marrow damage B6C3F1 mice (Inhalation) Bone marrow; Alteration of hemopoietic stem celL development Peripheral blood erythrocytes: Induction of micronuclei Induction oC MN Induction of SCEs Chromosomal aberrations Sperm abnormalities Dominant lethality C57B1/6 mice (lntraperltoneal injection) Bone marrow Increase in CA, SCE 4 Cunningham et al. 1986 + Tice et al. 1987 + Irons et al.* 1986a + Irons et al. 1986b + Leiderman et al. 1986 4 Jauhar et al. 1988 4 Tice et al. 1988 + HaeVett et al. 1988a + Sharlef et al. 1986 + " positive result; - negative result; ACT " average generation time; CA " chromosomal aberrations; MI " mitotic Index; MN mlcronucleated cells; 5CEs " sister chromatid exchanges HEALTH EFFECTS n USB1000 aaa VRD 0002037X75 35 2. HEALTH EFFECTS The indication that 1,3-butadiene can cause malignancy in the respiratory system was demonstrated by finding an increased incidence of alveolar/ bronchiolar cell carcinomas in mice after chronic exposure (Melnick et al. 1989; NTP 1984). Inhalation is not only the main route of exposure to 1,3-butadiene, but as indicated by toxicokinetic studies, it is also an important route of 1,3-butadiene metabolite excretion (Bolt et al. 1983). The metabolic pathway of 1,3-butadiene was first proposed by Malvoisin and Roberfroid (1982), and the metabolites, including 1,2-epoxybutene-3, have been considered to be the ultimate genotoxic agents (De Meester et al. 1980). It was demonstrated that 1,2-epoxybutene-3 showed carcinogenic activity following skin applications in Swiss mice (Van Duuren et al. 1963). High formation of epoxides was observed in the lung tissue of mice and rats incubated with 1.3- butadiene, in contrast to undetectable levels found in lung tissues from monkeys and humans (Schmidt and Loeser 1985). These findings support the theory that metabolites are responsible for the carcinogenic effect of 1.3- butadiene on the respiratory tract in rodents. An epidemiological study of mortality within a cohort of 6,678 male rubber workers examined the relationship between the deaths from malignant neoplasms and occupational exposure (McMichael et al. 1974). Significant increases of mortality due to malignancies of the stomach (SMR-187), prostate (SMR--142) and hemato-lymphopoietic system (SMR-226) were observed in the cohort. A subsequent study suggested an association between mortality from lymphatic leukemia with a history of working in multiple solvent-exposure jobs (McMichael 1975). However, in a follow-up case-control study an evaluation was made of the relationship of mortality excesses to specific jobs within the plant (McMichael et al. 1976). A clear association was found between the length of exposure to 1,3-butadiene and the occurrence of lymphatic and hematopoietic malignancy. The age-adjusted ratios of rates of exposure were 4.4 for those exposed for more than 2 years and 5.6 for those exposed for more than 5 years. An increased incidence of neoplasms of the lymphatic system was also found in other rubber workers studies (Matanoski et al. 1982, 1988, 1989, 1990). This finding was confirmed by Downs et al. (1987) in an epidemiological study of mortality among workers in a 1,3-butadiene monomer manufacturing facility that supplied 1,3-butadiene to two styrene-butadiene rubber plants. No significant excesses were observed for any cause of death except lymphosarcoma and reticulum cell sarcoma. When the cohort was subdivided into routine, nonroutine, and low-exposure groups, the standard mortality ratios (SMRs) were consistently elevated for these causes of death in all three groups. In an update of this study, the observation period of the cohort was extended for another 6 years (Divine 1989; 1990). The increased SMR for lymphosarcoma and reticulosarcoma was confirmed; however, there was an absence of an association between length of exposure and cancer risk, because all deaths occurred in those employed fewer than 10 years. These data are particularly important because the workers were reported not to be significantly exposed to other chemicals as was the case in the styrene- VRD 0002037176 36 2. HEALTH EFFECTS butadiene rubber plant studies. The lack of exposure duration and concentration data is a major deficiency of all epidemiological studies on 1.3- butadiene. As for evidence of the carcinogenicity of 1,3-butadiene in laboratory animals, 1,3-butadiene was shown to cause an altered regulation of stem cell development in B6C3F1 mice after an intermediate inhalation exposure (Leiderman et al. 1986). The changes in proliferation and differentiation of hematopoietic cells were similar to those usually preceding the onset of the expression of lymphoma in B6C3F1 mice. These data were supported by the increased incidence of malignant lymphoma in mice after chronic exposure to 1.3- butadiene (NTP 1984). An increased incidence (572) of thymic lymphoma in B6C3F1 mice was reported after exposure to 1,250 ppm 1,3-butadiene for 1 year (Irons 1989). This result agrees with the 60Z incidence found previously in this strain after similar exposure (NTP 1984). In contrast, these tumors were found only in 14% of treated NIH Swiss mice (Irons 1989). There were no histopathological differences in the tumors induced in these two strains of mice, but increased amounts of murine leukemia retrovirus (MuLV) envelope antigens were observed only in lymphomas from B6C3F1 mice (Irons et al. 1987b). Furthermore, when these tumors were cloned, an increased expression of the c-myc proto-oncogene was found (Irons et al. 1986c). MuLV retroviruses, which are expressed only in B6C3F1 mice but not in NIH Swiss mice, may play an important role in the lymphoma-type tumorigenesis. The extrapolation of these results to humans is difficult because human leukemia retroviruses (HTLV) have been found only in a small part of the population, and it is not known if their presence in humans would affect susceptibility to lymphoma the same way MuLV appears to affect development of lymphoma in mice exposed to 1,3-butadiene (Turnbull et al. 1988). However, the presence of other forms of neoplasms in experimental animals provides limited evidence for the potential carcinogenic nature of 1,3-butadiene in humans. It would therefore be prudent to consider that 1,3-butadiene or its metabolites have the potential to induce a carcinogenic response in humans as well. Multisite tumors were found among B6C3F1 mice after chronic exposure to 1,3-butadiene (NTP 1984), including hemangiosarcoma of the heart, malignant lymphoma, alveolar/bronchiolar adenoma and carcinoma, papilloma and carcinoma of the stomach, hepatocellular carcinoma, preputial gland carcinoma, Zymbal gland carcinoma, mammary gland carcinoma, and ovarian tumors. Multisite tumors, including Leydig cell adenomas, exocrine tumors of the pancreas, thyroid follicular cell adenoma, sarcoma of the uterus, mammary gland carcinoma, and Zymbal gland carcinoma were also found among Sprague-Dawley rats after chronic exposure to 1,3-butadiene (Owen et al. 1987). On the basis of the NTP data, IARC (1985) concluded that there is sufficient evidence for the carcinogenicity of 1,3-butadiene in experimental animals, but inadequate evidence for its carcinogenicity in humans. EPA (1985a) has classified 1,3-butadiene as a probable human carcinogen. However, the IARC and EPA conclusions were not based on the updated epidemiological data, as well as latest carcinogenicity and toxicokinetic studies in animals. Interspecies VRD 000203 7!77 37 2. HEALTH EFFECTS differences in metabolism between mice and primates and resulting higher susceptibility of mice to 1,3-butadiene toxicity may limit the relevance of studies in mice for human risk assessment. 2.5 BIOMARKERS OF EXPOSURE AMD EFFECT Biomarkers are broadly defined as indicators signaling events in biologic systems or samples. They have been classified as markers of exposure, markers of effect, and markers of susceptibility (NAS/NRC 1989). A biomarker of exposure is a xenobiotic substance or its metabolite(s) or the product of an interaction between a xenobiotic agent and some target molecule(s) or cell(s) that is measured within a compartment of an organism (NAS/NRC 1989). The preferred biomarkers of exposure are generally the substance itself or substance-specific metabolites in readily obtainable body fluid(s) or excreta. However, several factors can confound the use and interpretation of biomarkers of exposure. The body burden of a substance may be the result of exposures from more than one source. The substance being measured may be a metabolite of another xenobiotic substance (e.g., high urinary levels of phenol can result from exposure to several different aromatic compounds). Depending on the properties of the substance (e.g., biologic half-life) and environmental conditions (e.g., duration and route of exposure), the substance and all of its metabolites may have left the body by the time biologic samples can be taken. It may be difficult to identify individuals exposed to hazardous substances that are commonly found in body tissues and fluids (e.g., essential mineral nutrients such as copper, zinc, and selenium). Biomarkers of exposure to 1,3-butadiene are discussed in Section 2.5.1. Biomarkers of effect are defined as any measurable biochemical, physiologic, or other alteration within an organism that, depending on magnitude, can be recognized as an established or potential health impairment or disease (NAS/NRC 1989). This definition encompasses biochemical or cellular signals of tissue dysfunction (e.g., increased liver enzyme activity or pathologic changes in female genital epithelial cells), as well as physiologic signs of dysfunction such as increased blood pressure or decreased lung capacity. Note that these markers are often not substance specific. They also may not be directly adverse, but can indicate potential health impairment (e.g., DNA adducts). Biomarkers of effects caused by 1,3-butadiene are discussed in Section 2.5.2. A biomarker of susceptibility is an indicator of an inherent or acquired limitation of an organism's ability to respond to the challenge of exposure to a specific xenobiotic substance. It can be an intrinsic genetic or other characteristic or a preexisting disease that results in an increase in absorbed dose, biologically effective dose, or target tissue response. If biomarkers of susceptibility exist, they are discussed in Section 2.7, "POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE." s m m B M aaa 38 2. HEALTH EFFECTS 2.5.1 Biomarkers Used to Identify and/or Quantify Exposure to 1,3-Butadiene No studies were located regarding tissue, fluid, or excreta levels of 1,3-butadiene in humans. For the distribution of 1,3-butadiene and its metabolites in animal tissues see Section 2.3.2. Excretion of 1,3-butadiene metabolites was reported to be high in the urine of exposed monkeys (Dahl et al. 1990). Detection of urinary metabolites may be possibly used for biomarkers of exposure in humans. A linear accumulation of hemoglobin adducts was observed in B6C3F1 mice and Sprague-Dawley rats after intraperitoneal administration of radiolabeled 1.3- butadiene (Sun et al. 1989b). The lifetimes of these adducts were in agreement with the expected lifetimes for red blood cells in these animals. The determination of 1,3-butadiene-derived adducts in hemoglobin was proposed as a method to measure prior exposure(s) to this chemical. The investigators used liquid scintillation counting of radioactivity to detect the adducts; therefore, the assay cannot be used in humans. Furthermore, the formation of 1.3- butadiene-hemoglobin adducts has not been demonstrated in humans. DNA adducts were detected in the livers cf mice and rats exposed to radiolabeled 1.3- butadiene (Kreiling et al. 1986). Because humans are not likely to be exposed to radiolabeled 1,3-butadiene either under controlled conditions or in the environment, different methods for detecting and identifying the adducts would have to be developed in order to use hemoglobin or DNA adducts as a biomarker of exposure to 1,3-butadiene in humans. 2.5.2 Biomarkers Used to Characterize Effects Caused by 1,3-Butadiene No biomarkers used to characterize effects caused by 1,3-butadiene were identified. Dermal, ocular, and/or upper respiratory irritation can occur following 1,3-butadiene exposure (MCA 1974) and may alert the exposed individual. However, the effects are not specific for 1,3-butadiene exposure and may be caused by several other chemicals. 2.6 INTERACTIONS WITH OTHER CHEMICALS No studies were located regarding toxic effects of 1,3-butadiene in coexposure with other chemicals. In addition to 1,3-butadiene, workers in the rubber industry are exposed to other chemicals, including styrene and its metabolite, styrene oxide, which was also found to be mutagenic (Loprieno et al. 1978; Norppa et al. 1980; Pohlova et al. 1985; Watabe et al. 1978), Whether these other chemicals or their active metabolites have a synergistic harmful effect in humans is not known. 2.7 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE Black workers exposed to 1,3-butadiene in the production area of a styrene-butadiene (SBR) factory had a higher risk of mortality from lymphomas and leukemia than white workers (Matanoski et al. 1989). Furthermore, the 39 2. HEALTH EFFECTS exposure of black workers to 1,3-butadiene was also associated with a higher risk of cardiovascular diseases (Matanoski and Schwartz 1987). These limited data suggest that members of .the black population may be more susceptible to the effects of 1,3-butadiene, but the reason for the difference is not known. 2.8 MITIGATION OF EFFECTS This section will describe clinical practice and research concerning methods for reducing toxic effects of exposure to 1,3-butadiene. This section is intended to inform the public of existing clinical practice and the status of research concerning such methods. However, because some of the treatments discussed may be experimental and unproven, this section should not be used as a guide for treatment of exposures to 1,3-butadiene. When specific exposures have occurred, poison control centers and medical toxicologists should be consulted for medical advice. No specific antidotes for 1,3-butadiene are available; however, recommendations have been made for general treatment of intoxicated persons (Bronstein and Gurrance 1988; Stutz and Janusz 1988). First, the exposed individual should be removed from the contaminated area and contaminated clothing should be taken away. It has been suggested that exposed skin should be washed with soapy water and contaminated eyes flushed with water. Inhalation exposure to high 1,3-butadiene concentrations may result in narcosis leading to respiratory paralysis and death. Therefore, administration of oxygen has been used and ventilation has been assisted as needed in cases of 1,3-butadiene poisoning. Standard procedures have been used for the treatment of cardiac arrhythmias and pulmonary edema (Ellenhorn and Barceloux 1988). Although no specific data were located regarding the mitigation of effects of 1,3-butadiene once it has entered the bloodstream, studies on the mechanism of action are available that may provide insight into possible means of mitigating effects. Great interspecies differences were observed in the susceptibility to 1,3-butadiene-induced toxicity. Toxicity studies found mice to be extremely sensitive (Melnick et al, 1989, 1990). Studies on the metabolism of 1,3-butadiene demonstrated that the chemical is converted to its epoxy derivatives in the presence of NADPH and oxygen in microsomes (Malvoison and Roberfroid 1982). It was found that monkeys had the lowest levels of epoxy-metabolites in the blood after exposure to low 1,3-butadiene concentrations, while mice had the highest levels (Dahl et al. 1990; Sun et al. 1989a). The epoxides may be responsible for most toxic and carcinogenic effects caused by 1,3-butadiene exposure. The harmful effect of epoxidemetabolites is due to the formation of alkylation products with DNA; specifically, by the reaction with guanine (Bolt et al, 1984; Jellito et al. 1989). The determination of DNA adducts found in mice and rats was proposed as a measure of 1,3-butadiene exposure (Kreiling et al. 1986a; Sun et al. 1989b). The epoxides are detoxified by conjugation with glutathione and by further enzymatic transformation (Kreiling et al. 1988). A higher rate of 0002037179 o VRD 0002037180 40 2. HEALTH EFFECTS epoxide formation and a greater depletion of hepatic nonprotein sulfhydryl content in mice is probably responsible for their higher susceptibility to 1,3-butadiene toxicity. Since only after a substantial decrease of glutathione levels the macromolecular covalent binding is enhanced (Kreiling et al. 1988), sufficient availability of glutathione should mitigate the effects of 1,3-butadiene exposure. 2.9 ADEQUACY OF THE DATABASE Section 104(i)(5) of CERCLA as amended directs the Administrator of ATSDR (in consultation with the Administrator of EPA and agencies and programs of the Public Health Service) to assess whether adequate information on the health effects of 1,3-butadiene is available. Where adequate information is not available, ATSDR, in conjunction with the National Toxicology Program (NTP), is required to assure the initiation of a program of research designed to determine the health effects (and techniques for developing methods to determine such health effects) of 1,3-butadiene. The following categories of possible data needs have been identified by a joint team of scientists from ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that, if met, would reduce or eliminate the uncertainties of human health assessment. In the future, the identified data needs will be evaluated and prioritized, and a substance-specific research agenda will be proposed. 2.9.1 Existing Information on Health Effects of 1,3-Butadiene The existing data on health effects of inhalation, oral, and dermal exposure of humans and animals to 1,3-butadiene are summarized in Figure 2-3. The purpose of this figure is to illustrate the existing information concerning the health effects of 1,3-butadiene. Each dot in the figure indicates that one or more studies provide information associated with that particular effect. The dot does not imply anything about the quality of the study or studies. Gaps in this figure should not be interpreted as "data needs" information. As seen from Figure 2-3, information regarding acute systemic effects (respiratory tract irritation and narcotic effect), chronic systemic effects (cardiovascular and respiratory effects), genotoxicity and cancer exists for inhalation exposure in humans. No information was located regarding oral or dermal exposure of humans to 1,3-butadiene. Inhalation studies in animals provide data on death, systemic effects, immunologic effects, neurologic effects, genotoxicity, and carcinogenicity. Information concerning developmental and reproductive effects was also located. No information was located regarding effects in animals after oral or dermal exposure to 1,3-butadiene. vrd m m m i 41 2. HEALTH EFFECTS FIGURE 2-3. Existing Information on Health Effects of 1,3-Butadiene Existing Studies vrd 0 0 0 2 m m 42 2. HEALTH EFFECTS 2.9.2 Data Needs Acute-Duration Exposure. Acute inhalation exposure to very high concentrations of 1,3-butadiene may lead to narcosis and to death by respiratory paralysis in both humans and animals (Carpenter et al. 1944; Shugaev 1969). No studies were located that correlated the level of exposure with the first signs of toxicity in humans or animals. No NOAEL levels were identified in the available acute exposure studies. Developmental effects were seen in animals after exposure to the lowest concentration tested in acute studies (Hackett et al. 1987; Irvine 1981). A NOAEL value for developmental as well as systemic effects would be the most appropriate basis for the derivation of an acute inhalation MRL. No studies were located regarding effects following oral or dermal exposure, and no pharmacokinetic studies by the oral or dermal routes were located; therefore, it is not possible to predict if effects following oral or dermal exposure would be similar to those following inhalation exposure. Because 1,3-butadiene has been detected in soil off-gases at hazardous waste sites, inhalation exposure appears to be the greatest concern. However, it is not known if 1,3-butadiene is present in groundwater or soil at these hazardous waste sites because it is difficult to analyze these media for the compound. 1,3-Butadiene has been detected in industrial waste water and drinking water, and is quite soluble in water (735 ppm). Therefore, oral and dermal routes of exposure cannot be ruled out. Therefore, information concerning 1,3-butadiene toxicity by these routes of exposure would be useful. Because people living at or near these hazardous waste sites may be exposed for brief periods of time, more doseresponse data for acute exposures by all routes is considered to be important. Intermediate-Duration Exposure. No information is available regarding effects of 1,3-butadiene during intermediate-duration exposure in humans. No studies were located regarding effects in humans or animals following oral or dermal exposure to 1,3-butadiene, and pharmacokinetic data for these routes of exposure are insufficient to predict whether the disposition or toxicity of 1,3-butadiene following oral or dermal exposure would be similar to that following inhalation exposure. Therefore, information regarding the toxicity of 1,3-butadiene by the oral and dermal routes of exposure would be useful. Several studies on intermediate duration inhalation exposure to 1,3-butadiene have been conducted in animals (Crouch et al. 1979; Irons et al. 1986a; NTP 1984). Although NOAEL values for several systemic effects were recorded from those studies, an MRL was not derived, because 1,3-butadiene-related anemia was found in mice exposed to a lower concentration of 1,3-butadiene (Irons et al. 1986a). The observed changes were similar to those found in human preleukemic syndrome (Biemer 1983). The experimental results suggested that 1,3-butadiene exposure might interfere with normal bone marrow cell development. Further investigation of this topic could be valuable since epidemiological studies in humans indicate that hematopoietic tissue may be a possible target for 1,3-butadiene toxicity. This information is important in identifying sensitive subpopulations surrounding hazardous waste sites. VRD 008203T183 43 2. HEALTH EFFECTS Chronic-Duration Exposure and Cancer. Possible risk for hematological disorders was reported in humans after chronic inhalation exposure to 1,3-butadiene in occupational settings, but exposure levels are lacking, and exposure to other chemicals occurs in these settings (Checkoway and Williams 1982; McMichael et al. 1976). Well-conducted inhalation studies identified respiratory effects, liver necrosis, gonadal atrophy, and increased mortality in mice (Melnick et al. 1989, 1990; NTP 1984) and renal pathology and increased mortality in rats (Owen et al. 1987). Although NOAEL values were identified for systemic effects in mice exposed to low levels of 1,3-butadiene (Melnick et al. 1989, 1990), increased mortality was found at the same exposure levels. Therefore, no chronic MRL has been derived. Oral and dermal studies are lacking, and toxicokinetic data are insufficient to predict toxicity across routes of exposure. Therefore, information concerning the possible toxicity of 1,3-butadiene by these routes would be useful to identify the target organs and the thresholds for toxic effects. Further chronic inhalation studies in species other than mice using lower exposure levels might provide a NOAEL from which to derive a chronic inhalation MRL. This information is important because populations surrounding hazardous waste sites might be exposed chronically. Epidemiological studies in humans indicate a possible increase in carcinogenic risk from occupational exposure to 1,3-butadiene (Downs et al. 1987; Matanoski et al, 1982, 1989, 1990; McMichael et al. 1974, 1975, 1976; Meinhardt et al. 1982), This is supported by the information about mutagenic activity of 1,3-butadiene metabolites (De Meester et al. 1988) and by wellconducted chronic inhalation studies that provide information on carcinogenic effects of 1,3-butadiene in mice and rats (Melnick et al. 1989; NTP 1984; Owen et al. 1987). On the basis of the NTP data, IARC (1985) and EPA (1985a) concluded that there is sufficient evidence for the carcinogenicity of 1,3-butadiene in animals. IARC has classified 1,3-butadiene in group 2B, that is, as a possible human carcinogen. EPA has classified 1,3-butadiene as a probable human carcinogen. Further epidemiological investigation regarding the possible risk to humans would be useful. No chronic oral or dermal carcinogenicity studies in animals were located, and pharmacokinetic data are insufficient to predict a carcinogenic potential of 1,3-butadiene by these routes. Genotoxicity. Increased incidences of chromosomal aberrations and sister chromatid exchanges were found among petrochemical workers; however, the exposure was not solely to 1,3-butadiene (Zhou et al. 1986). 1,3-Butadiene has been tested in a number of in vivo studies using rats and mice following inhalation exposure (Cunningham et al. 1986; Tice et al. 1987). Inconclusive results from a dominant lethality study with rats (Hackett et al. 1988a) suggest that a repeat study should be performed. Information on the genotoxic effects of 1,3-butadiene is also obtained from in vitro studies in prokaryotic organisms (De Meester et al. 1980). These data sufficiently characterize the VRD 0002037184- 44 2. HEALTH EFFECTS genotoxic potential of 1,3-butadiene metabolites. However, reliable cytogenetic studies among exposed workers would be useful. These studies would provide the opportunity to determine if a correlation exists between the induction of chromosomal aberrations and sister chromatid exchanges in an individual and the concentration of 1,3-butadiene to which he is exposed. Reproductive Toxicity. The atrophy of gonads in mice after chronic inhalation exposure to 1,3-butadiene was reported (Melnick et al. 1989; NTP 1984). The fertility of rats, guinea pigs, or rabbits was reported to be unaltered by intermediate-duration inhalation exposure to 1,3-butadiene (Carpenter et al. 1944), but the age of these studies should be taken into consideration. Sperm head abnormalities were found in male mice exposed to 1,3-butadiene by inhalation (Hackett et al. 1988a, 1988b). No studies were located regarding reproductive toxicity of 1,3-butadiene by the oral or dermal routes in humans or animals, and pharmacokinetic data were insufficient to suggest the potential for 1,3-butadiene to cause reproductive effects by these routes of exposure. The potential for exposure of humans by the oral and dermal routes, however, is not known. Further information regarding the reproductive effects of 1,3-butadiene in animals such as multigeneration studies would be useful to estimate the possible risk for reproductive effects in humans. An epidemiological study among exposed populations concentrating on reproductive effects would be useful. Developmental Toxicity. No information on developmental toxicity in humans was located. A developmental study by the inhalation route in rats indicated growth retardation in the rat fetuses and an increase in major skeletal abnormalities at a concentration of 1,000 ppm of 1,3-butadiene (Irvine 1981). Furthermore, fetotoxicity was observed in mice at concentrations as low as 40 ppm 1,3-butadiene (Hackett et al.1987). More data on developmental toxicity in other species (at least one of them nonrodent) would be useful to identify possible developmental risk for humans. The developmental effects following other routes of exposure have not been studied, and pharmacokinetic data are insufficient to predict that responses would be similar to those by the inhalation route. Therefore, studies in animals to determine the possible developmental effects of 1,3-butadiene and the thresholds for these effects following oral and dermal exposure would strengthen confidence in the database obtained for these routes of exposure in other toxicity studies. Immunotoxicity. No persistent immunological defects were detectable after the intermediate-duration exposure of mice to 1,3-butadiene (Thurmond et al. 1986). The indications of disturbances in heraato- and lymphatopoietic stem cell regulations were observed after inhalation exposure of mice to 1,3-butadiene (Liederman et al. 1986). The high incidence of lymphoma among mice after the chronic exposure (NTP 1984) also indicates that the immune system is a target. A battery of immune function tests has not been performed 45 2. HEALTH EFFECTS in humans or in animals. More data regarding humans and animals would be useful for determining potential human immunotoxicity of 1,3-butadiene. Studies regarding skin sensitization with 1,3-butadiene are lacking. Neurotoxicity. Narcosis has been reported in humans (Sandmeyer 1981) and demonstrated in animals after acute inhalation exposure to very high levels of 1,3-butadiene (250,000 ppm) (Carpenter et al. 1944; Shugaev 1969). No reliable information was located regarding neurotoxicity due to chronic inhalation exposure or to oral or dermal exposure for any duration. Information regarding early, subtle signs of possible neurological effects with correlation to the exposure levels is lacking. A battery of neurological and neurobehavioral tests would be useful to better define the neurological endpoints. Epidemiological and Human Dosimetry Studies. Several epidemiological studies on health effects of 1,3-butadiene have been conducted (Case and Hosker 1954; Fox et al. 1974; Matanoski and Schwartz 1987; Matanoski et al. 1989; McMichael et al. 1974, 1975, 1976; Meinhardt et al. 1982). The serious limitation of these studies is that the cohorts of exposed workers were found in the rubber industry, in which the people were exposed to a mixture of various chemicals. More studies similar to the Downs et al.(1987) study, which was conducted among workers in a 1,3-butadiene manufacturing plant, ould be useful. Reliable dosimetry data on the exposed populations would be useful for good epidemiological comparisons. Efforts to improve estimates of past exposures and to more accurately define current exposure levels to 1,3-butadiene would be valuable. Epidemiological studies should concentrate on the possible carcinogenic effect of 1,3-butadiene in humans and on changes in hemato- and lymphatopoietic systems as possible targets for 1,3-butadiene induced toxicity. The data obtained from workers exposed occupationally to low concentrations of 1,3-butadiene could possibly be extrapolated to populations living near hazardous waste, sites. Biomarkers of Exposure and Effect. The determination of 1,3-butadiene derived adducts in hemoglobin of rats and mice exposed to 14C-1,3-butadiene has been proposed as a method to measure repeated exposures to this chemical (Sun et al. 1989). The investigators used liquid scintillation counting of radioactivity to detect the adducts. Because humans are not likely to be exposed to radiolabeled 1,3-butadiene in the environment, a different method for detecting adducts formation would have to be developed in order to use hemoglobin adducts to assess exposure in humans. Continued efforts to devise more specific early biomarkers of disease, especially hematological and oncological, would be valuable. No biomarkers of effects of 1,3-butadiene have been identified. Absorption, Distribution, Metabolism, and Excretion. In vitro studies have characterized some of the metabolism dynamics of 1,3-butadiene in animals S8I I 0100 0 sc C5 VRD 0002037186 46 2. HEALTH EFFECTS (Malvoisin and Roberfroid 1982; Malvoisin et al. 1979). Several toxicoklnetic studies on 1,3-butadiene metabolism in vivo have been conducted in rats and mice following inhalation exposure (Bolt et al. 1983; Bond et al. 1987; Kreiling et al. 196b; Shugaev 1969), but not following exposure by other routes. Thus, further studies in animals by the oral and dermal routes to determine possible target organs by these routes could be useful. Ethical considerations limit the testing of humans, but the development of methods to determine urinary and breath excretion of 1,3-butadiene and its metabolites by humans with known exposure to 1,3-butadiene may provide a means of monitoring humans for exposure. Comparative Toxicokinetics. The study by Schmidt and Loeser (1985) indicated that there is a difference between the capability of mouse and rat liver postmitochondrial fractions to produce 1,2-epoxybutene-3 after incubation with 1,3-butadiene. Furthermore, monkey and human postmitochondrial liver preparations catalyzed the formation of only a small amount of the epoxide. Higher levels of the toxic epoxides were found in blood of mice following 1,3-butadiene exposure as compared to monkeys (Dahl et al. 1990; Sun et al. 1989a). Species differences in the toxicokinetics of a chemical may account for differences in toxic responses. Analysis of the blood, breath, and urine of humans exposed to 1,3-butadiene for parent compound and metabolites over time would provide a greater knowledge of the human metabolic pathways. Qualitative and quantitative comparison of human metabolites with those of animals could help identify the most appropriate species to serve as a model for predicting toxic effects and mechanisms of action in humans. Mitigation of Effects. No specific information was located regarding mitigation of effects in 1,3-butadiene exposed individuals. The characteristic effects of 1,3-butadiene toxicity are known and nonspecific treatments for rescuing intoxicated persons have been recommended (Bronstein and Currance 1988; Stutz and Janusz 1988). The mechanism of toxicity involves a depletion of glutathione pool in the organs and binding of epoxidemetabolites to DNA (Bolt et al. 1983; Kreiling et al. 1988). The investigation of possible prevention of toxicity by obstruction of binding of active metabolites to DNA (possibly by increasing glutathione availability) would be useful. 2.9.3 On-going Studies The Board Draft of toxicology and carcinogenesis studies of 1,3-butadiene in B6C3F1 mice (NTP 1991) has been peer reviewed. However, the final draft incorporating the peer reviewers' comments has not yet been published. The results showed clear evidence of 1,3-butadiene carcinogenicity in mice exposed at 6.25, 20, 62.5, or 200 ppm for 2 years (6 hours/day, 5 days/week). Carcinogenic findings included neoplasms in the hematopoietic system, heart, lung, forestomach, liver, and Harderian gland in both sexes. Furthermore, VRD 0002037 187 47 2. HEALTH EFFECTS neoplasms were found In the preputial gland, brain, and kidneys of males and in the ovary and mammalian glands of females. Preliminary results from the NTP study were already published (Melnick et al. 1990) and were discussed in Sections 2.2.1.1, 2.2.1.2, 2.2.1.6, and 2.2.1.8. In addition, genotoxicity studies were performed by NTP (1991). 1,3-Butadiene induced gene mutations in Salmonella tvphimurium TA1535, but not in TA100, TA97, or TA98 strains. Negative results were also obtained in the mouse lymphoma assay. In contrast, chromosomal aberrations were induced at 625 ppm and sister chromatid exchanges at 62.5 ppm in bone marrow cells of mice exposed to 1,3-butadiene for 2 weeks (6 hours/day, 5 days/week). Several other studies on 1,3-butadiene were reported to be in progress (CMA 1991). Species differences in the metabolism between rodents and primates and the fate of toxic and/or mutagenic metabolites will be investigated. Similar information will be obtained in in vitro human studies. The mechanism of 1,3-butadiene toxicity to the bone marrow and hematopoietic system will be investigated in mice and humans. Furthermore, studies of the interaction of 1,3-butadiene and its metabolites with DNA will be performed. An abstract from the meeting of the Society of Toxicology reported interspecies differences in 1,3-butadiene toxicokinetics (Sabourin et al. 1991). Two major urinary metabolites of 1,3-butadiene were N-acetyl-S-(l(or 2)-[3-butene-2(or 1)-ol)cysteine (I) and N-acetyl-S-(4-butane-l,2-diol)cysteine (II) in all species tested. However, monkeys exposed to 1,3-butadiene produced predominantly metabolite II, while rodents produced 1-4 times as much of metabolite I as II. VRO 000793718a 49 3. CHEMICAL AMD PHYSICAL INFORMATION 3.1 CHEMICAL IDENTITY Data pertaining to the chemical identity of 1,3-butadiene are listed in Table 3-1. 3.2 PHYSICAL AND CHEMICAL PROPERTIES The physical and chemical properties of 1,3-butadiene are presented in Table 3-2. VRD 0002037189 50 3. CHEMICAL AND PHYSICAL INFORMATION TABLE 3-1. Chemical Identity of 1,3-Butadlene Characteristic Chemical name Synonyms Trade name(s) Chemical formula Chemical structure Information 1,3-Butadiene Butadiene; buta-1,3-diene; biethylene; bivinyl; vinylethylene; erythrene; a,a-butadiene; trans-butadiene; divinyl; pyrrolylene No data C,HS Reference CAS 1989 SANSS 1989; Chemline 1989; HSDB 1989; CAS 1989 CAS 1989 Identification numbers: CAS registry NIOSH RTECS EPA hazardous waste OHM/TADS D0T/UN/NA/IMC0 shipping HSDB NCI 106-99-0 EI9275000 RO377-0754 No data No data 181 C50602 CAS 1989 SANSS 1989 Miller 1978 Chemline 1989 Chemline 1989 CAS -- Chemical Abstracts Service NIOSH - National Institute for Occupational Safety and Health RTECS - Registry of Toxic Effects of Chemical Substances EPA - Environmental Protection Agency OHM/TADS -- Oil and Hazardous Materials Technical Assistance Data Base D0T/UN/NA/IMC0 - Department of Transportation/United Nations/North America/ International Maritime Consultive Organization HSDB - Hazardous Substance Data Bank NCI -- National Cancer Institute SANSS - Structure and Nomenclature Search System VRD 0002037190 51 3. CHEMICAL AND PHYSICAL INFORMATION TABLE 3-2. Physical and Chemical Properties of 1,3-Butadiene Property Information Reference Molecular weight Color Physical state Melting point Boiling point at 1 atm at 5 atm at 10 atm Density (liquid) at 20C Odor Odor threshold Water Air Solubility Water at 25C Organic solvents Partition coefficient Log octanol/water Log Kq,. (calculated from Kw) Vapor pressure at 25C Henry's law constant at 25"C (calculated) Autoignition temperature Flashpoint Flammability limits in air Conversion factors ppm (v/v) to mg/m3 in air (20C) mg/m3 to ppm (v/v) in air (20*C) Bioconcentration factor (calculated from KqW) Explosive limits 54.09 Colorless Gas -108. 9*C -4.4"C 47C 76C 0.6211 g/mL Mildly aromatic 0.0014 mg/L 1.0-1.6 ppm (recognition) 0.025 ppm (detection) 735 ppm Alcohol, ether, acetone, benzene, polar and nonpolar organic solvents 1.99 2.46 2.59 2100 mmHg 7.05xl0-2 atm-m3/mol 414*C -768C Extremely flammable 2.21 0.445 19 2-11.5% Weast et al. 1988 Sax and Lewis 1987 Sax and Lewis 1987 Weast et al. 1988 Weast et al. 1988 Windholz et al. 1983 Windholz et al. 1983 Weast et al. 1988 Sax and Lewis 1987 Amoore and Hautula 1983 Amoore and Hautula 1983 Verschueren 1983 McAuliffe 1966 Weast et al. 1988 Windholz et al. 1983 Hansch and Leo 1985 Lyman et al. 1982 Verschueren 1983 Daubert and Danner 1985 Hine and Mookerjee 1975 Sax and Lewis 1987 Sax and Lewis 1987 Miller 1978 IARC 1986 IARC 1986 Lyman et al. 1982 Kirshenbaum 1978 I6 U M 1 0 0 0 OHA 53 4. PRODUCTION. IMPORT, USE. AND DISPOSAL 4.1 PRODUCTION In 1985, 1,3-butadiene was the 36th highest-volume chemical produced in the United States (Sax and Lewis 1987). Domestic production of rubber-grade 1,3-butadiene in 1988 was approximately 3.2 billion pounds. Rubber grade monomer typically makes up 37% of the 1.8 billion pounds of the so-called 1.3- butadiene and butylene mixture produced in 1988 (Kirshenbaum 1978; USITC 1989), Similar data for 1987 were 2.9 and 1.2 billion pounds, respectively (USITC 1988). Total U.S. capacity for this compound stands at about 3,8 billion pounds (SRI 1991), although production capacity is highly dependent on the type of feedstock used (Chemical Marketing Reporter 1980). 1.3- Butadiene is currently produced by 11 manufacturers in Texas and Louisiana. These data are included in Table 4-1. 1,3-Butadiene is available as a liquified gas, with a stabilizer added for shipment (Kirshenbaum 1978). According to the Toxic Chemical Release Inventory (TRI 1989), 146 facilities manufactured or processed 1,3-butadiene in 1987. Of these, 142 facilities reported the maximum amount of 1,3-butadiene that they would have on site. A summary of these data is presented in Table 4-2. The quality of the TRI data must be viewed with caution because the 1987 data represent first-time reporting by these facilities. Only certain types of facilities were required to report. This is not an exhaustive list. Examination of the key chemical profiles on 1,3-butadiene (Chemical and Engineering News 1976, 1977, 1978, 1979, 1980, 1981, 1982, 1983, 1985, 1986) reveals that, during this time period, production volume, capacity, and prices have fluctuated in response to market pressures, which are outside of domestic use patterns. Descriptions such as "the odd world of 1,3-butadiene" (Chemical and Engineering News 1982), and "the maverick of the petrochemical business" (Chemical and Engineering News 1983) attest to the unpredictability of the 1.3-butadiene market. Recent estimates put the growth of domestic production at 0X-1X annually through 1992 (Chemical Marketing Reporter 1988). Except for a small amount of 1,3-butadiene produced by the oxydehydrogenation of n-butene, all the 1,3-butadiene produced in the United States is a co-product of ethylene manufacture, due in part to an increased demand for ethylene (Chemical and Engineering News 1985; Chemical Marketing Reporter 1988; IARC 1986; SRI 1991). In this process, feed streams ranging from light hydrocarbons to heavy gas oils (hydrocarbon fractions boiling in the approximate range of 315-480C) are cracked in the presence of steam at 700-9008C (Chemical and Engineering News 1986; Kirshenbaum 1978). The fraction of 1,3-butadiene produced by this process varies widely with the type of feedstock used and is lowest with low-boiling input streams (IARC 1986; Kirshenbaum 1978). The oxidative dehydrogenation of n-butene, used in the production of 1.3-butadiene, is a highly selective, irreversible process that involves VRD 0 0 2 03 7 1 92 54 4. PRODUCTION, IMPORT, USE, AND DISPOSAL TABLE 4-1. Current U.S. Producers of 1,3-Butadiene* Company Amoco Corp. Lyondell Petrochemicals Exxon Corp. Exxon Corp. Mobil Corp. Occidental Petroleum Corp. Occidental Petroleum Corp. Shell Oil Co. Shell Oil Co. Texaco, Inc. Texas Olefins Co. "Derived from SRI 1991; USITC 1989 Location Alvin, TX Channelview, TX Baton Rouge, LA Baytown, TX Beaumont, TX Chocolate Bayou, TX Corpus Christi, TX Deer Park, TX Norco, LA Port Neches, TX Houston, TX i t ii 55 4. PRODUCTION, IMPORT, USE, AND DISPOSAL TABLE 4-2. Facilities That Manufacture or Process 1,3-Butadiene* Stateb AL AR CA CO CT DE GA HI IA IL N ,.S KY LA MI MN MO MS MT NC NE NJ NY OH OK PA SC TN TX Number of facilities 1 1 12 2 1 2 3 1 2 7 3 3 6 16 1 1 1 2 2 2 1 2 3 15 3 (l)e 4 (l)e 1 3 49 (l)e Range of maximum amounts on site in thousands of pounds6 100-999 1-9 0-9,999 1-99 1,000-9,999 100-999 100-9,999 10-99 100-9,999 1-9,999 0.1-99 0.1-99 10-9,999 1-49,999 100-999 1,000-9,999 100-999 1-999 0.1-9 0-999 0-0.09 0-9 1-99 0-9,999 100-999 0.1-99 10-99 0-9,999 0-99,999 Activities and uses'd 7 1, 3 1. 3, 4, 5, 6- 7, 8, 9 3, 6, 7 7 1, 6. 7 7 1, 3, 6, 7 1, 3, 7 1, 3, 5, 6, 7 1, 3, 4, 6, 7, 8 1, 3, 5, 6. 7 1, 4, 5, 6, 7 1, 2, 3, 4, 5, 6, 7, 13 7 1, 6 7 3, 5. 7 1. 3, 6, 7 7, 8 3, 9, 12 1, 3, 5, 6, 7 2, 4, 6, 7 1, 3, 5, 6, 7, 8, 1, 3, 6, 7, 13 1, 3, 6, 7, 9 7 5, 6, 7 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 13 30 CTJ SS C=5 OJ SC VRD 000 20 3 7 H1 56 4. PRODUCTION, IMPORT, USE, AND DISPOSAL TABLE 4-2 (Continued) Stateb Number of facil ities Range of maximum amounts on site in thousands of pounds Activities and usesd VA WA WV 1 2 2 0.1-0.9 10-99 100-9,999 1, 4 1, 5, 6 7, 9 aTRI 1989 bPost office state abbreviations cData in TRI are maximum amounts on site at each facility. dActivities/Uses: 1. synthesis 2. import 3. for on-site use/processing 4. for sale/distribution 5. as a byproduct 6. as an impurity 7. as a reactant 8. as a formulation component 9. as an article component 10. for repackaging only 11. as a chemical processing aid 12. as a manufacturing aid 13. ancillary or other use Number in parentheses indicates facilities reporting "no data" regarding maximum amount of the substance on site. VRD 0 0 0 2 0 3 7 W 57 4. PRODUCTION, IMPORT, USE, AND DISPOSAL heating the starting material, air, and a suitable catalyst together at 400-450C (IARC 1986; Kirshenbaum 1978). The hydrogen released in the dehydrogenation step combines vith oxygen, producing large amounts of heat, which makes this process energy-efficient. Other products of this process include isobutylene, 1-butene, 2-butene, and n-butane. Purification of the crude C4 stream resulting from these processes cannot be achieved by a simple distillation due to the close boiling point of the various products (Kirshenbaum 1978). 1,3-Butadiene can be removed from the hydrocarbon stream by selective extraction with various solvents. These solvents include aqueous cupric ammonium acetate, acetonitrile, furfural, dimethylforraamide, N,N-dimethylacetamide, N-methylpyrrolidinone and li-methoxypropionitrile (IARC 1986; Kirshenbaum 1978). 4.2 IMPORT/EXPORT Large amounts of 1,3-butadiene are imported into the United States. The amount of 1,3-butadiene imported in 1987 represented 27X of the domestic production, a rise of 82% over the previous year (Chemical Marketing Reporter 1988). In 1986, approximately 500 million pounds were imported after a high of 900 million pounds in 1983 (Chemical and Engineering News 1983, 1986). As v' "h production volumes, no clear import trends can be deduced. Export omes of 1,3-butadiene from the United States are low, about 125 million pounds in 1986 (Chemical and Engineering News 1986), or about 4X of domestic production in 1987 (Chemical Marketing Reporter 1988). Exports may decrease with the expected increase in production of light hydrocarbons from petroleum sources in the North Sea, the Middle East and northern Africa. 4.3 USE 1,3-Butadiene is used as a monomer in the production of rubber and plastics, with approximately 75X going into the production of synthetic rubbers (Chemical and Engineering News 1986). 1,3-Butadiene uses can be broken down into the following categories: styrene butadiene rubber (SBR), 35%; polybutadiene, 22X; adiponitrile/hexamethylene diamine (HMDA), 12X; styrene-butadiene latex, 10X; neoprene rubber, 6X; ABS resins, 6X; exports, 4X; nitrile rubber, 3%; and other, 2% (Chemical Marketing Reporter 1988). It is also used extensively in copolymers including acrylics (Miller 1978). 4.4 DISPOSAL 1,3-Butadiene may be disposed of by incineration in a suitable combustion chamber or in a safe area. Gaseous 1,3-butadiene can be burned directly in most states; however, liquified 1,3-butadiene (in a compressed cylinder) must be converted to the gaseous state before burning (HSDB 1989). VRD 00020371 96 59 5. POTENTIAL FOR HUMAN EXPOSURE 5.1 OVERVIEW 1,3-Butadiene is a high-volume, volatile hydrocarbon used in the production of commercial plastics and rubbers. The chemical reactivity of this monomer is utilized in its transformation into polymeric materials. 1,3-Butadiene is also present in gasoline. 1,3-Butadiene may be released to the environment as an intentional or fugitive emission during its production, use, storage, transport, or disposal. Large amounts of this hydrocarbon are released to the atmosphere from commercial processes. According to the SARA Section 313 Toxic Release Inventory (TRI), an estimated total of 9.2 million pounds of 1,3-butadiene were released to the atmosphere from manufacturing and processing facilities in the United States in 1987 (TRI 1989). This total compares to a total release of approximately 9.6 million pounds to air, soil, water, public treatment works, and off-site areas during the same year. TRI data can be found in Table 5-1. The quality of the TRI data must be viewed with caution because the 1987 data represent first-time reporting by these facilities. Only certain types of facilities were required to report. This is not an exhaustive list. 1,3-Butadiene is also released to the atmosphere in motor vr* 'cle exhaust, cigarette smoke, the smoke of brush fires, the thermal b. xdown or burning of plastics, and by volatilization from gasoline. Large amounts of 1,3-butadiene are released to the atmosphere. Data on the detection of 1,3-butadiene in soil and water are scarce due to the lack of a reliable analytical method to detect this compound in these media. It has been qualitatively detected in drinking water. 1,3-Butadiene has been detected at three hazardous waste sites (View 1989). The states in which these hazardous waste sites are located can be found in Figure 5-1. 1,3-Butadiene is a highly volatile gas; therefore, it is expected to partition predominantly to the atmosphere. In the atmosphere, 1,3-butadiene is expected to undergo rapid destruction, primarily by photo-initiated reactions. The reaction with photochemically produced hydroxyl radicals has a calculated half-life of approximately 6 hours and is expected to be the dominant pathway for atmospheric removal. Destruction of atmospheric 1,3-butadiene by the gas-phase reaction with ozone and by the night-time reaction with nitrate radicals in urban areas is also expected to be significant. Limited data have been located on the fate of 1,3-butadiene in soil or water. Based on its physical properties, rapid volatilization of 1,3-butadiene from either soil or water to the atmosphere is expected to dominate over all other potential environmental processes. Studies performed with pure cultures indicate that 1,3-butadiene may be susceptible to microbial attack. Based on estimated values, 1,3-butadiene is not expected to adsorb significantly to soil or sediment, nor is it expected to bioconcentrate in P O T E N T IA L FOR HUMAN EXPOSURE J TAM.F. 5-1. Releases to the Rnvirnfmnt from Facilities That Manufacture or Process 1,3-But.adi eno* Stated No. of facllities At, 1 AR 1 CA 12 CO 2 CT 1 DE 2 CA 3 HI 1 1A 2 IL 7 IN 3 KS 3 KY 6 LA 16 MI 1 MN 1 MO 1 MS 2 WT 2 NC 2 NE 1 NJ 2 NY 3 OH 15 OK 3 PA 4 SC 1 TN 3 TX 49 VA 1 WA 2 WV 2 Air 3.4-3.4 0.3-0.3 0-2.1 0.3-0.6 41.3-41.3 24-78.3 105-403.5 0.5-0.5 175-278 0.1-113.8 0.4-40.2 0.2-0.4 1.7-161 0.1-150 63.5-63.5 0-0 0.2-0.2 0.5-2.2 0.3-0.9 0-9.6 o-o 0.1-0.1 0.1-65.8 0-146.8 0.1-1.9 0-115.6 14-14 9.9-640.2 0-960 0.1-0.1 4.2-5.7 6.1-700 Underground injection 0-0 0-0 0-0 0-0 0-0 0-0 0-0 No Data o-o 0-0 0-0 0-0.1 0-0 0-0 0-0 0-0 0-0 0-0 0-0 o-o 0-0 0-0 0-0 0-0 0-0 0-0 o-o o-o 0-0 0-0 o-o 0-0 Range of reported amounts released in thousands of pounds^ Water 0.3-0.3 o-o 0-0.3 0-0 0.1-0.1 0-0 0-0 0-0 0-0.1 0-0.3 0-0 0-0 0-0.1 0-0.2 0-0 0.1-0.1 0-0 0-0 0-0 0-0 o-o 0-0 0-0.1 0-0.3 0-0 0-0.3 0-0 o-o 0-430 0-0 0-0.1 0-0.1 Land 0-0 0-0 0-0 0-0 0-0 0-0 0-0 0-0 0-0 0-0 0-0 0-0 0-0.) 0-0. 1 0-0 0-0 0-0 o-o 0-0 0-0 0-0 o-o 0-0 0-0.1 0-0 0-0 0-0 0-0 0-2.9 0-0 o-o o-o Total environment 3.7-3.7 0.3-0.3 0-2.4 0.3-0.B 41.3-41.3 24-78.3 105-403.5 0.5-0.5 175-278 0.1-113.8 0.4-40.2 0.2-0.4 1.8-161 0.1-150 63.5-63.5 0.1-0.1 0,2-0,2 0.5-2.2 0.3-0.9 0-9.6 0-0 0.1-0.1 0.1-65.8 0,1-146.8 0.1-1.9 0.2-115.6 14-14 9.9-640.2 0-1.392 0.1-0.1 4.2-5.7 6.1-700 POTW transfer 0-0 0-0 0-0 O-o 0-0 0-0 0-0 0-0 0-0 0-0 o-o 0-0 0-0.3 0-0 0-0 o-o 0.1-0.1 0-0 0-0 0-0.1 0-0 0-0 0.1-0.1 0-36 0-0 0-0 0-0 0-0. 1 0-0 0-0 0-0 0-0 Off-site waste transfer .0.3-0.3 0-0 0-0.3 0-0 17-17 0-0 0-93 0-0 0-0 0-0 0-0 0-0.1 0-1.3 0-181.7 0-0 0-0 0.2-0.2 0-0 0-0 0-0 0-0 0-0 0-0.3 0-65.5 0-0 0-0 0-0 0-0 0-1.802 0-0 0-0 0-0 *'Data in TRI are maximum amounts released hv each facility. Quantities reported here have been rounded to the nearest hundred pounds, except those quantities * J million pounds, which have been rounded to the nearest thousand pounds. ^Publicly owned treatment works dFor.t. office state abbreviation pThe sum of all releases of the chemical to ait . land, water, and underf.i outid injection wells by a Riven facility. Li ILSB1000 dHA 61 5 POTENTIAL FOR HUMAN EXPOSURE * TOUEE 5 - 1 . FREQUENCY OF NPL SITES WITH 1,3-BUTADIENE CONTAMINATION D e riv e d fro m V iew 1909 SO 5=5 <sa SS <S9 ro OS oj co VRD 0 0 8 2 0 H l T r 62 5. POTENTIAL FOR HUMAN EXPOSURE fish or aquatic organisms; however, experimental data is necessary to verify these conclusions. Although 1,3-butadiene undergoes rapid destruction in the atmosphere, it is almost always present at very low concentrations in urban and suburban areas. Automobile exhaust is a constant source of 1,3-butadiene release to the atmosphere. Because of the compound's presence in the atmosphere, the general population is exposed to ppb levels of 1,3-butadiene through inhalation. Exposure to 1,3-butadiene may also occur from the inhalation of gasoline fumes, cigarette smoke, or possibly the smoke from wood fires. Possible ingestion of contaminated drinking water may also lead to low levels of exposure, although we do not know the concentration of this compound in water samples, nor do we have a good understanding of its frequency of detection. The levels of 1,3-butadiene in soil are not known. Dermal exposure to low levels of 1,3-butadiene may occur for members of the general population if they spill gasoline on themselves. Elevated levels of exposure for the general population may occur for those near its site of manufacture or facilities where it is made into polymeric materials. Occupational exposure to 1,3-butadiene is expected to be limited to those working at facilities that manufacture 1,3-butadiene or convert it into commercial polymers. Exposure by inhalation is expected to be the dominant pathway for exposure. Theoretically, dermal exposure to liquified 1,3-butadiene could occur during an explosion of a pressurized storage tank or some other catastrophic event; however, no such accidents have been reported in the available literature. 5.2 RELEASES TO THE ENVIRONMENT 5.2.1 Air The dominant sources for the release of 1,3-butadiene to the atmosphere are fugitive or accidental emissions during its manufacture, use, transport, and storage. Low levels of 1,3-butadiene are constantly emitted to the atmosphere from many sources including exhaust from motor vehicle engines using petroleum-based fuels. A correlation of data from the EPA Air Toxic Emission Inventory with industrial source codes (SIC) indicates that volatile emissions of 1,3-butadiene are associated with 14 different industrial classifications, which are dominated by rubber and chemical products (Pacific Environmental Services 1987). Fugitive emissions of 1,3-butadiene from seals, valves, vents, flanges, and the like in petrochemical plants manufacturing this compound were estimated to be 1,112 metric tons/year (Hughes et al. 1979). The authors believed that this level of release was lower than that released by refineries. Emissions of 1,3-butadiene from equipment leaks and process vents in 1984 were estimated at 3.8 million pounds/year during its production, 5 million pounds/year during the synthesis of styrene-butadiene copolymers, \ j j ; ( < | j 4 j i j j I ! j ' j i i nrzrTvtmm VRD 0002037200 63 5. POTENTIAL FOR HUMAN EXPOSURE 900.000 pounds from polybutadiene production, and 86,000 pounds from neoprene/chloroprene production (Mulling 1990). According to the TRI (1989), 155 facilities that manufacture or process 1.3- butadiene released an estimated 9,205,532 pounds of this compound to the atmosphere in 1987. The largest air emission from a single facility was 960.000 pounds. The quality of the TRI data must be viewed with caution because the 1987 data represent first-time reporting by these facilities. Only certain types of facilities were required to report. exhaustive list. TRI data can be found in Table 5-1. This is not an 1,3-Butadiene is a component of motor vehicle exhaust; this is a constant source of release to the atmosphere (Stump and Dropkin 1985). In high-traffic areas, the release of 1,3-butadiene to the atmosphere occurs continually. In a recent study, it was measured in the exhaust of typical automobiles and light trucks using both winter and summer gasoline formulations and accounted for up to 0.12X of total hydrocarbon emissions (Stump et al. 1989). An earlier study determined that the concentration of 1,3-butadiene in automobile exhaust was 20-60 ppb (Neligan 1962). 1,3-Butadiene has also been detected in the exhaust of diesel engines (Hayano et al, 1985) and high-altitude jet aircraft engines operating under simulated conditions (Katzman and Libby 1975). 1,3-Butadiene has also been identified in modern formulations of t `.aded gasolines (Sigsby et al. 1987) and may be released to the atmosphere bj direct volatilization from the fuel. There are several minor sources for the release of 1,3-butadiene to the atmosphere; all involve the thermal breakdown of other materials. 1.3- Butadiene has been detected as a component of the sidestream smoke from cigarettes (Bartle et al. 1969; Blomberg and Widmark, 1975). The average amount of 1,3-butadiene in sidestream cigarette smoke is 205-361 pg/cigarette (Brunnemann et al., 1990), with an average airborne yield of 400 ^g/cigarette (Lofroth et al. 1989). The burning of plastics or rubber has been shown to release small amounts of 1,3-butadiene (Miller 1978). In a test designed to simulate a real-life electrical overload condition, 1,3-butadiene was detected when polyurethane coated wire was heated to 250C for 40 minutes (Rigby 1981). 1,3-Butadiene has also been measured as a component of the smoke from a brush fire (Stephens and Burleson 1969), and as a stack emission from waste incinerators (Junk and Ford 1980). The concentrations of 1,3-butadiene were not presented in these studies. 5.2.2 Water Very limited data on release of 1,3-butadiene to environmental waters were located in the available literature. According to the TRI (1989), 155 facilities that manufacture or process 1,3-butadiene discharged an estimated total of 432,857 pounds of 1,3-butadiene to surface water in 1987. A single facility was responsible for 430,000 pounds of this discharge. 0002037201 64 5. POTENTIAL FOR HUMAN EXPOSURE 73 O Transfer of 1,3-butadiene to publicly owned treatment works (POTWs) amounted to 56,490 pounds in 1987 (TRI 1989). The quality of the TRI data must be viewed with caution because the 1987 data represent first-time reporting by these facilities. Only certain types of facilities were required to report. This is not an exhaustive list. 5.2.3 Soil Limited data on releases of 1,3-butadiene to soil were located in the available literature. According to the TRI (1989), 155 facilities that manufacture or process 1,3-butadiene released an estimated total of 3,672 pounds of 1,3-butadiene to land in 1987. However, the quality of the TRI data must be viewed with caution because the 1987 data represent first time reporting by these facilities. Only certain types of facilities were required to report. This is not an exhaustive list. 5.3 ENVIRONMENTAL FATE 5.3.1 Transport and Partitioning Experimental data on the partitioning of 1,3-butadiene in the environment were not located in the available literature. The following discussion on the partitioning of 1,3-butadiene in the environment is based on the physical and chemical properties of this compound. The estimation techniques used in this discussion are well-established in the literature; however, without adequate experimental data, we do not know exactly how this compound will behave in the environment. The high volatility of this compound suggests that it will partition predominantly to the atmospheric compartment, where it is not expected to be adsorbed to particulate matter to any significant extent (Eisenreich et al., 1981). An estimated Henry's law constant of 7.05xl0"2 atm/m3-mol at 25C can be obtained using the method of Hine and Mookerjee (1975). Based on this value, the half-life for volatilization of 1,3-butadiene from a model river 1 m deep, flowing at 1 m/sec, with a wind velocity of 3 m/sec is 2.2 hours (Lyman et al. 1982) . Based on an experimental log octanol/water partition coefficient of 1.99 (Hansch and Leo 1985), a calculated soil adsorption coefficient of 288 (Lyman et al. 1982) suggests that adsorption to sediment and suspended organic matter will not be a significant fate process. From the log octanol/water partition coefficient, a calculated bioconcentration factor of 19 (Lyman et al. 1982) indicates that 1,3-butadiene will not bioconcentrate in fish and aquatic organisms to any significant extent. However, no experimental data have been located to verify these theoretical values. If released to soil, 1,3-butadiene is expected to volatilize rapidly from either moist or dry soil to the atmosphere. This follows from the estimated VRD 0002037202 65 5. POTENTIAL FOR HUMAN EXPOSURE Lack of any appreciable adsorption to soil, and consideration of 1,3-butadiene's calculated Henry's law constant for moist soil or its vapor pressure, 2,100 mmHg at 25C (Daubert and Danner 1985), for dry soil. Both values suggest a rapid rate of Volatilization from their respective media. The calculated soil adsorption coefficient of 288 (Hansch and Leo 1985; Lyman et al. 1982) suggests that 1,3-butadiene may display moderate mobility in soil (Swann et al. 1983). However, the expected rapid rate of volatilization and the possibility of rapid degradation in soil suggest that there is little potential for 1,3-butadiene to leach into groundwater. But until adequate groundwater monitoring for 1,3-butadiene has been performed, the partitioning of 1,3-butadiene in soil cannot be adequately addressed. 5.3.2 Transformation and Degradation 5.3.2.1 Air Butadiene is a reactive, electron-rich chemical that is expected to undergo rapid reactions with the electrophilic oxidants typically present in the atmosphere: ozone, photochemieally produced hydroxyl radicals, nitrate radicals, and molecular oxygen. Among these, the most rapid reaction in the atmosphere is with photochemieally produced hydroxyl radicals. The atmospheric destruction of 1,3-butadiene by photo-initiated processes has been established empirically by early studies. These studies typically involved irradiating urban air samples in atmospheric chambers of varying complexity and monitoring the disappearance of each constituent. Using this technique, 1,3-butadiene, at an average concentration of 12.4 ppb, disappeared in 6 hours when irradiated with natural sunlight during October (Kopczynski et al. 1972). In another study, a half-life of 2 hours was determined for the atmospheric removal of 1,3-butadiene using natural sunlight in October or November (Altshuller et al. 1970). In smog chamber studies, the sunlight oxidation of 1,3-butadiene led to the formation of fairly potent eye irritants, suggesting destruction of this compound with concomitant formation of oxygenated species (Dimitriades et al. 1975; Heuss and Glasson 1968). It is believed that the destruction of 1,3-butadiene occurs by photo-initiated bimolecular processes rather than direct photochemical degradation (Kopczynski et al. 1972). It is important to note that the rate of destruction of 1,3-butadiene when it was irradiated with natural light depended on the time of day in which the irradiation occurred. Furthermore, these studies were performed in October and November, when the amount and the intensity of available sunlight is diminished over that of summer months; thus, these values probably represent the high end of the compound's atmospheric lifetime. The individual processes responsible for the destruction of 1,3-butadiene in the atmosphere are discussed below. Numerous studies have determined the rate constant for the gas-phase reaction of 1,3-butadiene with photochemieally produced hydroxyl radicals 1 I! I- 'I 66 5. POTENTIAL FOR HUMAN EXPOSURE (Atkinson 1985; Atkinson and Aschmann 1984; Atkinson et al. 1977, 1979; Maldotti et al. 1980). The experimental rate constant 6.85xl0-11 cm3/ molecule-sec at 26*C (Atkinson et al. 1977) is representative. Given an average hydroxyl radical concentration of 5x10s molecule/cm3 (Atkinson 1985), the half-life for this second-order process is 5.6 hours. In an attempt to classify the potential for atmospheric destruction of organic compounds by hydroxyl radicals, a rating system based on nonreactive methane (class I) to highly reactive compounds (class V) was established (Darnall et al. 1976). In this classification system, 1,3-butadiene was assigned between classes IV and V, signifying its high reactivity towards photochemically produced hydroxyl radicals. Gas-phase 1,3-butadiene also reacts with ozone in the atmosphere. Rate constants ranging from 6.7xl0"18 to 8.4xl0-16 cm3/molecule-sec at 25C have appeared in the literature (Atkinson and Carter 1984; Jaspar et al. 1974). Using an average atmospheric ozone concentration of 7xlOu molecules/cm3 (Atkinson and Carter 1984), half-lives ranging from 1.4 to 1.7 days can be calculated for this second-order process. Therefore, the reaction of 1,3-butadiene with ozone is expected to contribute to the overall destruction of atmospheric 1,3-butadiene. The initial products from the reaction of 1,3-butadiene with ozone are acrolein, formaldehyde, acetylene, ethylene, and formic anhydride (Niki et al. 1983). All of these products are susceptible to secondary reactions with ozone and other atmospheric oxidants. 1,3-Butadiene can also be destroyed in the atmosphere by the reaction with ground-state, triplet oxygen. Rate constants for this addition reaction range from 1.9xl0'u to 2.07xl0~11 cm3/molecule-sec (Atkinson and Pitts 1977; Gaffney and Levine 1979; Nip et al. 1979), in a reaction that appears to be essentially independent of temperature (Nip et al. 1979). Given the average atmospheric concentration of oxygen of 2.54xl04 molecules/cm3 (Graedel et al. 1986), the half-life for the destruction of 1,3-butadiene by this process can be calculated as 15-16 days. Although this reaction will not be significant under conditions where the facile pathways described above are operating, it may occur under conditions where they are not. The night-time degradation of 1,3-butadiene is also expected to occur via the gas-phase reaction with nitrate radicals; this tends to be significant in urban areas, where the concentration of this oxidant is typically higher than in rural areas (Altshuller and Cohen 1964; Gay and Bulfalini 1971; Maldotti et al. 1980). A rate constant of 5.4X10'1* cm3/molecule-sec at 22C has been determined for this reaction. This corresponds to a half-life of 14.9 hours using an average atmospheric nitrate radical concentration of 2.4x10 molecule/cm3 (Atkinson et al. 1984), typical of mildly polluted urban centers. Acrolein has been identified as a primary product of this reaction. In summary, there are four gas-phase pathways that can destroy 1,3-butadiene in the atmosphere. Depending on local conditions, any one or all of these reactions may occur. Destruction of atmospheric 1,3-butadiene by IB IL tB IB B B AHA. VRD 0002037204 67 5. POTENTIAL FOR HUMAN EXPOSURE the gas-phase reaction with photochemically produced hydroxyl radicals is expected to be the dominant photo-initiated pathway. Destruction by nitrate radicals is expected to be a significant night-time process in urban areas. 5.3.2.2 Water Data on the degradation of 1,3-butadiene In aquatic systems are limited. Experimental data are restricted to microbial degradation studies performed under aerobic conditions. The bulk of these data were obtained from isolated bacterial strains, not with mixed microbial populations typically found in natural systems. 1,3-Butadiene biodegraded when inoculated with methane utilizing, or methanotrophic, organisms under aerobic conditions. Cell suspensions of these, bacteria oxidized 1,3-butadiene to 3,4-expoxybutene (Hou et al. 1979, 1980; Patel et al. 1982a). None of the authors reported further degradation of the epoxide to the corresponding diol. Bacteria isolated from lake water and raised on propane also oxidized 1,3-butadiene to 3,4-expoxybutene (Hou et al. 1983). 1,3-Butadiene was listed as a synthetic organic chemical that should degrade in a biological sewage treatment system, provided that suitable acclimation could be achieved, although no experimental details were provided (Thom and Agg 1975). A Nocardia species isolated from water and soil completely degraded 1,3-butadiene to acetic acid under aerobic conditions (Watkinson and Somerville 1976). The proposed route for this degradation involves initial stereospecific epoxidation to but-3-ene-l,2-epoxide followed by ring opening to but-3-ene-l,2-diol, oxidation to the corresponding a-keto acid (2-ketobutyrate-3-ene), loss of C02 to acrylic acid, hydroxylation to 2-hydroxypropionic acid, oxidation to pyruvic acid, and loss of C02 to acetic acid. This pathway is described in Figure 5-2 (Verschueren 1983; Watkinson and Somerville 1978). Although this pathway is reasonable, experimental evidence establishing the formation of all the key intermediates was not provided. Most importantly, cleavage of the initially formed epoxide was not rigorously established. No data were located on the biodegradation of 1,3-butadiene under anaerobic conditions. 5.3.2.3 Soil As is the case for the degradation of 1,3-butadiene in water, very limited data on the destruction of this compound in soil could be located in the available literature. The experimental data obtained from pure culture studies on the microbial degradation of 1,3-butadiene suggest that this compound can biodegrade in soil. Methane-utilizing bacteria isolated from the soil of an oil refinery epoxidized 1,3-butadiene under aerobic conditions (Hou et al. 1979; Patel et al. 1979, 1982a, 1982b). Cell suspensions of Mycobacterium obtained from \1 and raised on ethylene oxidized 1,3-butadiene under aerobic conditions; VRD 0002037205 68 5. POTENTIAL FOR HUMAN EXPOSURE FIGURE 5-2. Catabolic Pathway for the Biodegradation of 1,3-B. byNorcardia Cultures in Aqueous Media* CH2 CM - CM = CM 2 1,3-buladiono NAOH + Oj O n CM?~ CM - C - COOH 2-kelobutyrialo-3-eno '' CH2 CM - COOH acrylic acid CH3COOH acetic acid co2 O /\ ch2- ch-ch-cm2 bul-3-one-t ,2-epoxido I on 1 CH2= CM - CM - CM-.- CM but-3-enQ-l ,2-dioI OH I CH3- CM - COOH 2-hydroxypropionic acid I O II ch3-c-coom pyruvic acid Source: Verschueren 1983; Watkinson and Somerville 1976 VRD 0002037206 69 5. POTENTIAL FOR HUMAN EXPOSURE however, cultures raised on ethane or succinate did not (DeBont et al. 1979). Microorganisms isolated from soil (Nocardia. Mycobacterium. Xanthobacter. and Pseudomonas) and raised on gaseous alkenes oxidized 1,3-butadiene to the corresponding epoxide under aerobic conditions (VanGinkel et al. 1987). These bacteria may convert the initially formed epoxide to the diol, although no evidence was presented to support this point. A Nocardia species isolated from soil and water degraded 1,3-butadiene under aerobic conditions to acetic acid (Watkinson and Somerville 1976). The proposed sequence for this transformation is described in Section 5.3.2.2 and presented in Figure 5-2. No data on the degradation of 1,3-butadiene under anaerobic soil conditions were located in the available literature. 5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 5.4.1 Air In an analysis of the ambient air monitoring data for the United States contained in published and unpublished experimental reports from 1970 to 1987, Shah and Heyerdahl (1988) compiled median daily concentrations for volatile organic compounds. For 1,3-butadiene, the median concentrations are 0.29 ppb i urban areas, 0.32 ppb in suburban areas, and 0.10 ppb in rural areas. The value for rural areas must be interpreted carefully, as it is based on only two data points. The suburban and urban values are based on 196 and 385 data points, respectively. Representative data on the concentration of 1,3-butadiene in urban and remote areas can be found in Table 5-2. Reports on the detection of 1,3-butadiene in urban areas have also been published from areas monitored in the Netherlands (Guicherit and Schulting 1985), Australia (Mulcahy et al. 1976), and South Africa (Louw et al. 1977). On a monitoring trip in 1986, the Texas Air Control Board (1990) measured ambient air concentrations within a mile of a petrochemical complex in Allendale, Texas, suspected of exceeding air quality limits. The average concentration of 1,3-butadiene was 100 ppb, with the highest daily and hourly average measured at 143 and 905 ppb, respectively. A 1989 monitoring trip to Port Neches, Texas, found that air samples within 1 mile of another petrochemical complex had a highest 1 hour average 1,3-butadiene concentration of 642 ppb and a highest 12-hour average concentration of 240 ppb. This manufacturing plant was also suspected of exceeding air quality limits. The highest single value for 1,3-butadiene measured in this study was 1,740 ppb. Residential areas were located near the monitoring stations used in these two studies. 1,3 - Butadiene has been detected in indoor air samples. The concentrations of 1,3-butadiene in a tavern were 11 and 19 /ig/m3 (4.98 and 8.60 ppb) in two separate studies, while the outside air concentration was less than or equal to 1 pg/m3 (0.45 ppb) at the same time (Lofroth et al. 789). The difference in the indoor versus outdoor concentration may be * P O T E N T IA L FOR HUMAN EXPOSURE TABLE 5-2. Detect ion of 1,3- Butadiene in Air Media type/location Sampling dates No. of samples Concentration (rmh> Range Moan Reference Urban Houston, TX Los Angeles, CA Riverside, CA Los Angeles, CA Boone, NC Boone, NC (downtown) Boone, NC (outskirts) 1973 1974 1974 1968 1965-66 1960 1981-82 9 7 4 NS 8 16 3 3 3 ND-150" 8.0-57 ND-8.4 NS ND-2.0 ND-9 ND-0.34* 0.34-5.0 0.11-0.22 33.4" 27.2 3.0 12.4" NS 3.1 0.11 4.2 0.15 Lonneman et al. 1979 * Kopczynski et al. 1972 Stephens and Burleson 1967 Neligan 1962 Seila et al. 1984 Remote Roan Mt., NC 1981-82 3 ND-0.22* 0.74 Seila et al. 1984 Grandfather Mt., NC 3 ND-0.15 0.37 Linville Gorge, NC 3 ND-0.45 0.19 "Data reported in ppbC (parts per billion carbon). 1 ppb = 1.12 ppbC (54.1 ppb/48.4 ppbC) Converted to ppb using the conversion factor ND below detection limit NS - not stated i0zn0ZD0B aya VRD 0002037208 71 5. POTENTIAL FOR HUMAN EXPOSURE ascribed to the presence of 1,3-butadiene in cigarette smoke. The concentration of 1,3-butadiene in a smoke-filled bar was 2.7-4.5 **g/m3 (1.2-2.0 ppb) (Brunneraann et al. 1990). 1,3-Butadiene was also detected in a public building in Riverside, California, in 1965 at a concentration of 9.0 ppb, although its source was not specified (Stephens and Burleson 1967). 5.4.2 Water Limited data on the occurrence of 1,3-butadiene in water were located in the available literature. 1,3-Butadiene was found in 1 of 204 water samples taken in 1975--76 from surface waters near known industrialized areas across the United States. The single positive sample was obtained in the Carquinez Strait, Posta Corta, California, at an approximate concentration of 2 ppb (Ewing et al. 1977). No specific data on its presence in drinking water, such as monitoring dates or concentration, were located; however, 1,3-butadiene has been qualitatively detected in U.S. drinking water (EPA 1978; Kraybill 1980). 5.4.3 Soil No data on the occurrence of 1,3-butadiene in soil were located in the t liable literature. 5.4.4 Other Environmental Media 1,3-Butadiene is used to manufacture synthetic rubber and plastics that are frequently used for food packaging. Because residual 1,3-butadiene may be present in the polymers used to make the containers, both the packaging and the food contained therein have been analyzed. In one study, 1,3-butadiene at a concentration of 8--9 ng/g (ppb) was detected in 3 of 3 brands of olive oil packaged in 1,3-butadiene rubber-modified acrylonitrile-acrylic bottles (McNeal and Breder 1987). Analysis of the bottles themselves found 1,3-butadiene residues as high as 6600 ng/g (ppb). Soft-plastic packaging tubs used as containers for potato salad, cottage cheese, and yogurt had residual 1,3-butadiene levels in the range 21-1700 ng/g (ppb). However, no 1,3-butadiene was detected in any of the food packed in these containers (detection limit 1 ppb). Chewing gum made with a 1,3-butadiene rubber base did not show residual traces of this diene (McNeal and Breder 1987). Softplastic margarine tubs from five major name brands in the United Kingdom contained 1,3-butadiene residues ranging from 5 to 310 /ig/kg (ppb), but none of the monomer was detected in the margarine samples themselves (detection limit 0.2 Mg/kg) (Startin and Gilbert 1984). The authors concluded that migration of the 1,3-butadiene monomer from plastic packaging to food is unlikely to present a problem. Residual levels of 1,3-butadiene in food containers are closely regulated by the Food and Drug Administration. VRD 006203 7 20 9 72 5. POTENTIAL FOR HUMAN EXPOSURE 5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE 1,3-Butadiene is almost always present in the air at low levels due to its emission from motor vehicles. Therefore, the general population is probably routinely exposed to ppb levels of this compound, although adverse health effects have not been noted at this level of exposure. Exposure to 1.3- butadiene by the general population is expected to be dominated by inhalation. Low level exposure by ingestion of contaminated drinking water may also occur as 1,3-butadiene has been qualitatively detected in U.S. drinking water supplies (EPA 1978; Kraybill 1980). Inhalation of 1,3-butadiene by the general population may also occur due to other sources. 1,3-Butadiene has been identified in cigarette smoke; therefore, smokers and those nearby are exposed to this compound (Lofroth et al. 1989; Bartle et al. 1969; Blomberg and Widmark 1975; Brunnemann et al. 1990). Limited data suggest that 1,3-butadiene is present in the smoke from brush fires (Stephens and Burleson 1969), suggesting that inhalation of the smoke from wood fires will lead to low level exposure to 1,3-butadiene. Its presence in waste incinerator emissions (Junk and Ford 1980) suggests that exposure to the general population may occur for those living nearby. Due to its presence in gasoline formulations (Sigsby et al. 1987; Stump et al. 1989), members of the population who pump their own gasoline may inhale small amounts of 1,3-butadiene. The concentration of 1,3-butadiene in gasoline vapor is 4.4 ppb (IARC 1986). Small amounts of 1,3-butadiene are produced by the thermal degradation of polyurethane-coated wire, an event that may occur during an electrical overload (Rigby 1981). The thermal degradation of other 1.3- butadiene-based plastics or rubbers may produce 1,3-butadiene (Miller 1978) , also leading to low-level exposure of the general population by inhalation. If the mean daily urban air concentration of 1,3-butadiene is 0.29 ppb, as determined in an analysis and compilation of experimental reports of ambient monitoring data obtained from 1970 to 1987 (Shah and Heyerdahl 1988), a nonoccupational daily intake of 12.8 per person can be obtained based on an average human intake of 20 m3 air/day. No data are available that quantify general population exposure to 1.3-butadiene by other routes of intake, such as ingestion of contaminated drinking water. Given that residues of 1,3-butadiene have been found in plastic and rubber food containers and in a few samples of the food contained in these containers (McNeal and Breder 1987), very low-level exposure to the general population may occur by ingestion of contaminated foods packaged in these containers. 1,3-Butadiene has been identified as a constituent of modern gasoline formulations, and the general population may receive dermal exposure to 1,3-butadiene upon contact with gasoline (Sigsby et al. 1987), although the rate of absorption of 1,3-butadiene through the skin has not been investigated. VRD 0802037210 73 5. POTENTIAL FOR HUMAN EXPOSURE According to the National Occupational Exposure Survey (NOES) conducted by NIOSH between 1980 and 1983, 9,456 workers, of which 286 are women, were estimated to be exposed to 1,3-butadiene (NIOSH 1989). The NOES database does not contain information on the frequency, concentration, or duration of exposure of workers to any chemicals listed therein. These surveys provide only an estimate of the number of workers potentially exposed to chemicals in the workplace. Occupational exposure to 1,3-butadiene is expected to be limited to inhalation of this compound, although dermal contact with liquified 1,3-butadiene may occur during a large spill, tank explosion, pipeline rupture, or similar catastrophic event, although no reports of this type have been reported in the available literature. Specific industrial classifications or job descriptions involving exposure to 1,3-butadiene are provided below. A field study conducted in the process control room of a styrenebutadiene rubber plant using 12 different sampling locations concluded that the 1,3-butadiene concentration ranged from 0.044 to 6.5 ppm over a 3-day testing period (Jones and Harris 1983). Health hazard evaluation surveys conducted by NIOSH at six facilities utilizing 1,3-butadiene found that the air concentration ranged from 0.06 ppm to 39 ppm. These facilities manufactured helmets, visors, synthetic rubber, rubber tires and tubes, itomotive weather stripping, braided hoses, or plastic components for rcraft. According to this NIOSH report, workers involved in the industrial classifications listed in Table 5-3 have been potentially exposed to 1.3-butadiene (NIOSH 1984). A walk-through survey of 11 monomers, 17 polymers, and 2 end-user plants found that personal exposures ranged from less than 0.006 ppm to 374 ppm (Fasen et al. 1990). Environmental sampling at two Texas styrene butadiene rubber plants had time-weighted average concentrations of 1,3-butadiene ranging from 0.11 to 4.17 ppm (mean, 1.24 ppm) and 0.34 to 174 ppm (mean, 13.5 ppm) for samples taken in 1977 (Meinhardt et al. 1982). The range of 1,3-butadiene concentrations for individuals at the plant is given in Table 5-4. 5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES High levels of exposure to 1,3-butadiene are likely to be limited to those resulting from an occupationally related use of this compound. Inhalation is the most likely route of high exposure to 1,3-butadiene. 1.3-Butadiene is stored and transported in pressurized tanks, and it is possible that high levels of exposure by inhalation or dermal contact with the liquified gas may occur during the loading and unloading of these tanks, or by the accidental rupture of these tanks. However, no such accidents have been reported in the available literature. VRD 000203T?11 74 5. POTENTIAL FOR HUMAN EXPOSURE TABLE 5-3. Industrial Workers Potentially Exposed to 1,3-Butadiene" Industry Paper and allied products t Chemicals and allied products Petroleum and coal products Rubber and plastic products Primary metal industries Fabricated metal products Machinery, except electrical Electrical equipment and supplies Transportation equipment I Instruments and related products Miscellaneous manufacturing industries Miscellaneous business services i Medical and other health services Derived from NIOSH 1984 Number of workers exposed 1,221 44,980 84 9,086 55 96 1210 121 175 145 2244 5339 493 i.. VRD 0007 03 72 12 75 5. POTENTIAL FOR HUMAN EXPOSURE TABLE 5-4. Air Concentrations of 1,3-Butadiene in a Styrene Butadiene Rubber Plant* Affected individuals Technical services personnel Production foreman Head production operator Production operator Operator helper Pipefitter Electrician Maintenance mechanic Carpenter Common laborer Instrument man rived from Meinhardt et al. 1982 Concentration (ppm) 0.21-114.6 1.16 (1 sample) 0.25-69.61 0.23-33.21 0.26-1.81 0.18-1.78 0.18-0.34 0.19-44.38 0.20-30.60 0.17-8.22 0.17-174.14 VRD 880 20 372 13 76 5. POTENTIAL FOR HUMAN EXPOSURE 5.7 ADEQUACY OF THE DATABASE Section 104(i)(5) of CERCLA as amended directs the Administrator of ATSDR (in consultation with the Administrator of EPA and agencies and programs of the Public Health `Service) to assess whether adequate information on the health effects of 1,3-butadiene is available. Where adequate information is not available, ATSDR, in conjunction with the National Toxicology Program (NTP), is required to assure the initiation of a program of research designed to determine the health effects (and techniques for developing methods to determine such health effects) of 1,3-butadiene. The following categories of possible data needs have been identified by a joint team of scientists from ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that, if met, would reduce or eliminate the uncertainties of human health assessment. In the future, the identified data needs will be evaluated and prioritized, and a substance-specific research agenda will be proposed. 5.7.1 Data Needs Physical and Chemical Properties. The physical and chemical properties of 1,3-butadiene are well documented (Sax and Lewis 1987; Windholz et al. 1983), and its environmental fate can be estimated from these properties (Lyman et al. 1982). Experimental verification of these calculated values used to determine the partitioning of 1,3-butadiene in the environment are necessary to establish accurate levels of human exposure. Production, Import/Export, Use, and Disposal. The trends in the production and use of 1,3-butadiene are well documented (Kirsheribaum 1978; Chemical Marketing Reporter 1980; USITC 1988), and there do not appear to be any critical information gaps. 1,3-Butadiene monomer does not occur in most products used in the home, although residues of this compound in commercial packages, especially food containers (McNeal and Breder 1987), are not well described. Although it is clear that the majority of 1,3-butadiene is released to the atmosphere (TRI 1989), data on the release of 1,3-butadiene are not well correlated with specific sources. The disposal of 1,3-butadiene appears to be a straightforward process (HSDB 1989); however, the amount of , 1,3-butadiene released or destroyed annually is not well documented. As the TRI program is improved, this type of information will become more readily available. According to the Emergency Planning and Community Right-to-Know Act of 1986, 42 U.S.C. Section 11023, industries are required to submit chemical release and off-site transfer information to the EPA. The Toxic Release Inventory (TRI), which contains this information for 1987, became available in May of 1989. This database will be updated yearly and should provide a list of industrial production facilities and emissions. VRD 0002037214 77 5. POTENTIAL FOR HUMAN EXPOSURE Environmental Fate. The fate of 1,3-butadiene in the atmosphere is well understood (Atkinson 1985; Atkinson and Carter 1984; Atkinson et al. 1984; Kopczynski et al. 1972). The fate of 1,3-butadiene in soil and water is not well understood, and partitioning from these media has to be determined from the physical and chemical properties of this compound (Lyman et al. 1982). A reliable method capable of detecting 1,3-butadiene in soil and water was not located in the available literature, and it is not clear whether 1,3-butadiene is absent from these media or simply not yet detected. The persistence of 1,3-butadiene in soil and water is not known, and the degree of partitioning from one environmental compartment to another can only be estimated. Exposure via ingestion or dermal contact to populations surrounding hazardous waste sites cannot, therefore, be accurately determined. Experimental data that addresses the partitioning of 1,3-butadiene in the environment, its potential to enter drinking water supplies, and its lifetime in soil and water are necessary to completely characterize the environmental fate of this compound. Bioavailability from Environmental Media. Numerous toxicokinetic and toxicity studies in humans and animals have demonstrated the bioavailability of 1,3-butadiene from air. No data on the bioavailability of 1,3-butadiene from other sources (water or soil, for example) were located in the available literature. In conjunction with the data needs for determining 1,3-butadiene in environmental media, bioavailability studies from environmental media would be useful. Food Chain Bioaccumulation. In theory, 1,3-butadiene is not believed to bioconcentrate significantly in fish and aquatic organisms; thus, it is not expected to biomagnify in the food chain (Hansch and Leo 1985; Lyman et al. 1982). No data addressing this point, however, were located in the available literature. Validation of these theories by valid experimental studies will aid in establishing a quantitative determination of 1,3-butadiene exposure to the general public. Exposure Levels in Environmental Media. Data on the levels of 1,3-butadiene in environmental media are limited. Extensive data on the occurrence of 1,3-butadiene in ambient air samples are available (Shah and Heyerdahl 1988), but recent data appear to be lacking. Further, current correlations between the levels of 1,3-butadiene in the atmosphere and its sources of release are not available. Levels of 1,3-butadiene at hazardous waste sites are not available. Data on the occurrence of 1,3-butadiene in water samples are limited (Ewing et al. 1979). The presence of 1,3-butadiene in drinking water has been noted in the literature, but no concentrations or frequency of detection are available (EPA 1978; Kraybill 1980). The concentration of 1,3-butadiene in soil, water, and air at hazardous waste sites is not known (CLPSD 1989); therefore, the potential for exposure to populations residing nearby cannot be established. The development of reliable analytical techniques for the analysis of 1,3-butadiene in soil and VRD 000 20 3 7 2 1 5 78 5. POTENTIAL FOR HUMAN EXPOSURE water will establish unambiguously the levels at which this compound is found in environmental media. Exposure Levels in Humans. Limited data on levels of occupational exposure to 1,3-butadiene were available in the literature; however, occupational exposure to this compound appears to be limited to a readily definable group of industrial classifications (NIOSH 1984, 1989). Exposure levels for the general population are not well defined. No data on its presence in human tissue were located. Studies that correlate personal exposure with daily activities are necessary to establish adequately exposure levels for 1,3-butadiene. Biological monitoring studies cannot be performed until acceptable experimental techniques are developed. Exposure levels for those living near hazardous waste sites are not available and should be established. Exposure Registries. No exposure registries for 1,3-butadiene were located. This compound is not currently one for which a subregistry has been established in the National Exposure Registry, but it will be considered in the future when chemical selection is made for subregistries to be established. The information that is amassed in the National Exposure Registry facilitates the epidemiological research needed to assess adverse health outcomes that may be related to the exposure to the compound. 5.7.2 On-going Studies On-going atmospheric monitoring studies for 1,3-butadiene performed by S. Sigsby have been identified (EPA 1989b), although no other specific information was provided. Remedial investigations and feasibility studies conducted at the NPL sites known to be contaminated with 1,3-butadiene could add to the available database on exposure levels in environmental media, exposure levels in humans, and exposure registries, and may increase knowledge regarding the fate of 1,3-butadiene in the environment. No other long-term research studies pertaining to the environmental fate of 1,3-butadiene or to occupational or general population exposures to 1,3-butadiene were identified. VRD 0002037216 79 6. ANALYTICAL METHODS The purpose of this chapter is to describe the analytical methods that are available for detecting and/or measuring and monitoring 1,3-butadiene in environmental media and in biological samples. The intent is not to provide an exhaustive list of analytical methods that could be used to detect and quantify 1,3-butadiene. Rather, the intention is to identify well-established methods that are used as the standard methods of analysis. Many of the analytical methods used to detect 1,3-butadiene in environmental samples are the methods approved by federal agencies such as EPA and the National Institute for Occupational Safety and Health (NIOSH). Other methods presented in this chapter are those that are approved by groups such as the Association of Official Analytical Chemists (AOAC) and the American Public Health Association (APHA). Additionally, analytical methods are included that refine previously used methods to obtain lower detection limits, and/or to improve accuracy and precision. 6.1 BIOLOGICAL MATERIALS No standardized method to test for the presence of 1,3-butadiene in biological materials presently exists. Only a limited number of techniques have been employed to determine this compound in biological materials. An early method for the determination of 1,3-butadiene in blood was developed in 1944 (Miller 1978). It involves heating a blood sample containing iodine pentoxide to 200C, followed by determining the amount of 1,3-butadiene present by titrating any free iodine (produced during the reduction of iodine pentoxide) with sodium thiosulfate. This method is not specific to 1,3-butadiene; thus, its usefulness in obtaining an accurate indication of human exposure to 1,3-butadiene is unlikely. Techniques for the determination of ^C-labeled 1,3-butadiene in rat or mice blood and tissue after experimental exposure to enriched material have appeared in the literature (Bond et al. 1986, 1987). 1,3-Butadiene is removed from the sample matrix by vacuum distillation or by sparging with an inert gas. The desired material is recovered by collection in a cryogenic trap. The amount of 1,3-butadiene can then be ascertained by measuring the activity in the traps by scintillation counters. This technique cannot be applied to measure 1,3-butadiene exposure for the general population. However, the sample preparation step may be amenable to standardized gas chromatography (GC) techniques presently used in the determination of other organic compounds. A technique for the determination of 1,3-butadiene in margarine samples was reported by Starting and Gilbert (1984). The margarine sample is placed in a vial, sealed, and heated to 70#C where it is allowed to equilibrate for 1 hour. The amount of 1,3-butadiene in the sample is determined by withdrawing a headspace sample, and injecting it directly into a GC equipped with a mass spectrometer (MS) detection system. Quantitation is obtained by VRD 008 2 0372 1 7 80 6. ANALYTICAL METHODS comparison of the peak height to that of a standard of known concentration. The sensitivity of this method allows quantitation down to 0.001 mg/kg (1 ppb). A similar headspace technique was used to test for the presence of butadiene in olive oil, vegetable oil, and yogurt samples (McNeal and Breder 1987). 6.2 ENVIRONMENTAL SAMPLES Standardized methods for determining 1,3-butadiene in environmental samples are limited to air samples, as no methodology has been described for analyzing this compound in water or soil samples (EPA 1982, 1986, 1988a). A representative list of the methods available for the determination of 1,3-butadiene in air samples can be found in Table 6-1. The determination of 1,3-butadiene in personal air can be obtained using the procedure outlined in NIOSH Method 1024 (NIOSH 1987), which is described below. The air sample is obtained by passing a known volume of air (3-25 L) through a set of tandem coconut charcoal tubes, which adsorb 1,3-butadiene and remove it from the air stream. The collected 1,3-butadiene is then removed from the adsorption tube by extraction with methylene chloride. Injection of the methylene chloride solution into a GC equipped with a flame ionization detector (FID) separates 1,3-butadiene from any interfering compounds that may be present. The choice of chromatography column for this determination is not crucial, as long as it cleanly separates 1,3-butadiene from other compounds. The estimated quantitation limit of this method is 0.02 ppm, with an applicable range of 1-480 fig per sample (approximately 0.02-8.7 ppm) for a 25 L sample. The precision of this method appears to change as a function of the concentration being measured, due to desorption efficiencies changing as a function of sample concentration. With increasing concentration, the preparation of a standard becomes more difficult. In NIOSH Method 1024, quantitation of 1,3-butadiene is accomplished by comparing the area under the sample's response signal to that of a known amount of 1,3-butadiene. The preparation and injection of a gaseous 1,3-butadiene standard is a difficult procedure; it must be performed carefully or erroneous results will occur. Sample storage appears to dramatically affect the results of the measurement. Samples stored at -4C displayed an average recovery of between 93X and 98X over a 21-day period, while samples stored at room temperature ranged from 61X to 95%. Literature methods for the determination of 1,3-butadiene in personal air samples overcome some of these problems (Hendricks and Schultz 1986; Lunsford 1987; Lunsford and Gagnon 1987). 1,3-Butadiene, along with other volatile hydrocarbons, has been found in ambient air samples by a technique that uses cryogenic concentration before GC analysis. This technique is performed by collecting a large volume of air in TABLE 6-1. Analytical Methods for Determining 1,3-Butadiene in Environmental Steeple* Sample matrix Preparation method Personal air Air Air Air (real time) Pass air through charcoal tube CHjClj desorption Collect air in Tedlar bag, concentrate on Tenax cartridge, thermal desorption Pass air through charcoal tube, solvent desorption Draw air into 12 foot sampling loop, direct injection FID flame ionization detector GC " gas chromatography MS " mass spectrometry Analytical method GC/FID GC/FID Sample detection limit 0.02 ppm No data Percent recovery No data No data Reference NIOSH 1987 Stump and Dropkin 1985 GC/MS GC/MS No data No data No data No data Texas Air Control Board 1990 Texas Air Control Board 1990 A N A L Y T IC A L METHODS 8 IILIBUBB AHA GHA 82 6. ANALYTICAL METHODS a specially designed bag or other sampling container and concentrating the volatile components by condensation at low temperatures. The sample is separated into its components by GC and quantified with an internal standard. Numerous variations of this method were found in the literature (Lonneman et al. 1979; Nellgan 1962; Stephens and Burleson 1967, 1969; Stump and Dropkin 1985) . 6.3 ADEQUACY OF THE DATABASE Section 104(i)(5) of CERCLA as amended directs the Administrator of ATSDR (in consultation with the Administrator of EPA and agencies and programs of the Public Health Service) to assess whether adequate information on the health effects of 1,3-butadiene is available. Where adequate information is not available, ATSDR, in conjunction with the National Toxicology Program (NTP), is required to assure the initiation of a program of research designed to determine the health effects (and techniques for developing methods to determine such health effects) of 1,3-butadiene. The following categories of possible data needs have been identified by a joint team of scientists from ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that, if met, would reduce or eliminate the uncertainties of human health assessment. In the future, the identified data needs will be evaluated and prioritized, and a substance-specific research agenda will be proposed. 6.3.1 Data Needs Methods for Determining Biomarkers of Exposure and Effect. No standardized method for the determination of biomarkers of exposure and effect for 1,3-butadiene was located. A recent paper has demonstrated that 1,3-butadiene forms a hemoglobin adduct in mice and rats (Sun et al. 1989b). However, the 1,3-butadiene used in this study was tagged with a radioactive tracer, a technique which is only rarely utilized in the determination of environmental exposure in humans. In conjunction with the data needs discussed in Chapter 2, a method to monitor the formation of a 1,3-butadiene adduct with human hemoglobin needs to be established. The development of an analytical technique to measure this biomarker of exposure can then be achieved. Once a unique biomarker has been identified and an experimental technique to detect it has been established, a quantitative assessment of routes and levels of human exposure to 1,3-butadiene can be undertaken. No known biomarkers of effect specifically for 1,3-butadiene have been reported, but recent advances have been made (Gallagher 1989; Weston et al. 1989) in 32P-post labelling and other DNA adduct assays. VRD 0002037220 63 6. ANALYTICAL METHODS Methods for Determining Parent Compounds and Degradation Products in Environmental Media. Data on the determination of 1,3-butadiene in environmental media were limited. 1,3-Butadiene in air samples has been detected by techniques routinely used for detecting volatile hydrocarbons (Stump and Dropkin 1985; Texas Air Control Board 1990). Procedures accepted for the determination of volatile hydrocarbons in other environmental media (soil, water, sediment, plants, etc.) may also be suitable for 1,3-butadiene. This question can be answered only by the data obtained from properly designed experiments. The information will assist In determining the prevalence of this compound in the environment and aid in a quantitative determination of human exposure to 1,3-butadiene. 6.3.2 On-going Studies On-going studies performed by J. Pau at EPA's Atmospheric Research and Exposure Assessment Laboratory in Research Triangle Park, NC, on new analytical methods for the determination of 1,3-butadiene have been identified (EPA 1989b), although no other specific information was provided. VRD 08020 3 7 2 2 1 85 7. REGULATIONS AND ADVISORIES The International Agency for Research on Cancer (IARC) and national and state regulations and guidelines pertinent to human exposure to 1,3-butadiene are summarized in Table 7-1. 1,3-Butadiene has been deleted from the list of extremely hazardous substances (EPA 1988b). VRD 000203722,2 86 7. REGULATIONS AND ADVISORIES TAHT-T 7-1. -Regulations and Guideline* Applicable to 1,3-Butadiene Agency Description Information References INTERNATIONAL IARC Carcinogenic classification Group 2B" NATIONAL Regulations: a. Air: EPA OAQPS OSHA Intent to list under Section 112 of Clean Air Act PEL PEL STEL b. Nonspecific media: EPA OERR Reportable quantity (statutory) Threshold planning quantity Yes 1000 ppm (transitional limit; in process of 6(b) rulemaking) 2 ppm (proposed) 10 ppm (proposed 1 lb 10,000 lb Guidelines: a. Air: ACGIH NIOSH TLV RL 10 ppm (suspected human carcinogen) Carcinogen; lowest feasible concentration b: Other: EPA STATE Carcinogenic classification Inhalation slope factor Inhalation unit riskc Group B2^ 1.6 (mgAg/day)'1 6.2x10"* (ppb)*1 2.8x10-* (iig/m3)-1 Regulations and Guidelines: a. Air: Connecticut Kentucky Massachusetts Michigan North Carolina Nevada Virginia Acceptable ambient air concentrations 22,000 ME/m* (8'hr evg) 11 mg/m3 (8-hr avg) 0.0350 jig/m3 (24-hr avg) 0.0030 p%/a? (annual) 0.0350 ps/m3 (annual) 52.40 mg/m3 (8-hr avg) 220.0000 M8/m3 (2>-hr avg) IARC 1985,1987 EPA 1985b (40 CFR 61.01) OSHA 1989 (29 CFR 1910.2926) OSHA 1990 (29 CFR 1910.32736) EPA 1987 (40 CFR 300 and 355) ACGIH 1989 NIOSH 1986 EPA 1985a IRIS 1991 NATICB 198B State of Kentucky 1986 NATICH 1988 NATICH 1988 NATICH 1988 NATICB 1988 NATICB 1988 "Group 2B: Possible human carcinogen ^Group B2: Probable human carcinogen cThe unit risk should not be used if the air concentration exceeds 7.2 ppb, since above this concentration, the slope factor may differ from that stated (IRIS 1991). ACGIH " American Conference of Governmental Industrial Hygienists; EPA " Environmental Protection Agency; IARC " International Agency for Research on Cancer; IRIS " Integrated Risk Information System; NATICH - National Air Toxics Information Clearinghouse; NIOSH - National Institute for Occupational Safety and Health; OAQPS " Office of Air Quality Planning and Standards; OERR * Office of Emergency and Remedial Response; OSHA * Occupational Safety and Health Administration; PEL * Permissible Exposure Limit; REL " Recommended Exposure Limit; STEL m Short-Term Exposure Limit; TLV * Threshold Limit Value; TWA Time-Weighted Average u il m iw i 87 8. REFERENCES ACGIH. 1989. Threshold limit values and biological exposure indices for 1989-1990. American Conference of Governmental Industrial Hygienists. Cincinnati, OH, 14. Altshuller, AP. 1965. Reactivity of organic substances in atmospheric photooxidation reactions. Environ Health Ser PHS Publ No 999-AP-14. Altshuller AP, Cohen IR. 1964. Atmospheric photooxidation of the ethylene nitric oxide system. Int J Air Water Pollut 8:611-632. Altshuller AP, Kopczynski SL, Lonneman WA, et al. 1970. measuring photochemical reactions in atmospheric samples. 4:503-506. A technique for Environ Sci Technol Amoore JE, Hautala E. 1983. Odor as an aid to chemical safety: Odor thresholds compared with threshold limit values and volatilities for 214 industrial chemicals in air and water dilution. J Appl Toxicol 3:272-290. *Arce GT, Vincent DR, Cunningham MJ, et al. 1989. The in vitro and in vivo genotoxicity of 1,3-butadiene and metabolites. Haskell Laboratory for Toxicology and Industrial Medicine, E.I. Du Pont de Nemours and Company, Inc. Atkinson R, 1985. Kinetics and mechanisms of the gas-phase reactions of the hydroxyl radical with organic compounds under atmospheric conditions. Chem Rev 85:69-201. Atkinson R, Aschmann SM. 1984. Rate constants for the reaction of the hydroxyl radicals with a series of alkenes and dialkenes at 2951 K. International Journal of Chemical Kinetics 16:1175-1186. Atkinson R, Carter WPL. 1984. Kinetics and mechanisms of gas-phase reactions of ozone with organic compounds under atmospheric conditions. Rev 84:437-470. Chem Atkinson R, Pitts JN Jr. 1977. Absolute rate constants for the reaction of oxygen(3P) atoms with allene, 1,3-butadiene, and vinyl methyl ether over the temperature range 297-439 K. J Chem Phys 67:2492-2495. Atkinson R, Perry RA, Pitts JN Jr. 1977. Absolute rate constants for the reaction of hydroxyl radicals with allene 1,3-butadiene and 3-methyl-l-butene over the temperature range 299-424 K. J Chem Phys 67:3170-3174. Cited in text. VRD 0002037774 88 8. REFERENCES Atkinson R, Darnall KR, Lloyd AC, et al. 1979. Kinetics and mechanisms of the reactions of the hydroxyl radical with organic compounds in the gas phase. Adv Photochem 11:375-488. Atkinson R, Aschmann SM, Winer AM, et al. 1984. Kinetics of the gas-phase reactions of N03 radicals with a series of dialkenes, cycloalkanes, and monoterpenes at 2951 K. Environ Sci Technol 18:370-375. Barnes D, Bellen J, DeRosa C, et al. 1988. Reference dose (RfD): description and use in health risk assessments. Volume I, Appendix A: Integrated risk information system supportive documentation. Washington, DC; U.S. Environmental Protection Agency, Office of Health and Environmental Assessment. EPA/600/8-86/032a. Bartle KD, Bergstedt L, Novotny M, et al. 1969. Tobacco chemistry II. Analysis of the gas phase of tobacco smoke by gas chromatography-mass spectrometry. J Chromatogr 45:256-263. Biemer JJ. 1983. The preleukemic syndrome. Ann Clin Lab Sci 13:156-162. Blomberg L, Widmark G. 1975. Separation of fresh tobacco on a packed polar gas chromatographic column prior to on-line analysis by gas chromatographymass spectrometry using a non-polar capillary column. J Chromatogr 106:59-71. Bolt HM, Schmiedel G, Filser JG, et al. 1983. Biological activation of 1,3-butadiene to vinyl oxirane by rat liver microsomes and expiration of the reactive metabolite by exposed rats. J Cancer Res Clin Oncol 106(2):112-116. Bolt HM, Filser JG, Stormer F. 1984. Inhalation pharmacokinetics based on gas uptake studies. V. Comparative pharmacokinetics of ethylene and 1,3-butadiene in rats. Arch Toxicol 55(4):213-218. Bond JA, Dahl AR, Henderson RF, et al. 1986. Species differences in the disposition of inhaled butadiene. Toxicol Appl Pharmacol 84(3):617-627. Bond JA, Dahl AR, Henderson RF, et al. 1987. Species differences in the distribution of inhaled butadiene in tissues. Am Ind Hyg Assoc J 48(10):867-872, Bond JA, Martin OS, Birnbaum LS, et al. 1988. Metabolism of 1,3-butadiene by lung and liver microsomes of rats and mice repeatedly exposed by inhalation to 1,3-butadiene. Toxicol Lett 44:143-151. Brodzinsky R, Singh HB. 1982. Volatile organic chemicals in the atmosphere: An assessment of available data. Menlo Park, VA: Atmospheric Science Center, SRI International. VRD 0002037225 89 8. REFERENCES Bronstein and Currance. 1988. Emergency care for hazardous materials exposure. Washington, DC: The C.V. Mosby Company, 155-156. Brunnemann KD, Kagan MR, Cox JE, et al. 1990. Analysis of 1,3-butadiene and other selected gas-phase components in cigarette mainstream and sidestream smoke by gas chromatography-mass selective detection. Carcinogenesis 11:18631868. Burroughs GE. 1979. NIOSH Health Hazard Evaluation Determination. Aircraft Corporation, Vero Beach, FL. Report No. 78-110-585. NTIS PB80-196-702. Piper Carassiti V, Bignozzi CA, Chiorboli C, et al. 1980. Photochemical oxidation of the butadiene-nitrogen oxides-acrolein system. Proc 1st European Symp Phys Chera Behav Atmos Pollut, 221-225. Carey PM. 1987. Air toxics emissions from motor vehicles. 86. NTIS PB88-115001. EPA/AA/TSSS/PA- Carpenter CP, Shaffer CB, Weil CS, et al. 1944. Studies on the inhalation of 1,3-butadiene; with a comparison of its narcotic effect with benzol, toluol, and styrene, and a note on the elimination of styrene by the human. J Ind Hyg Toxicol 26(3):69-78. CAS. 1989. Chemical Abstracts Service, Chemical Abstracts Registry File [Database], September 8, 1989. Case RAM, Hosker ME. 1954. Tumor of the urinary bladder as an occupational disease in the rubber industry in England and Wales. Br J Prev Soc Med 8:3950.* *Checkoway H, Williams TM. 1982. A hematology survey of workers at a styrene-butadiene synthetic rubber manufacturing plant. Am Ind Hyg Assoc J 43(3):164-169. Chemical and Engineering News. 10, 12. 1976. Key Chemicals Profile Butadiene. May Chemical and Engineering News. November 7, 14. 1977. Key Chemicals Profile Butadiene. Chemical and Engineering News. November 20, 15. 1978. Key Chemicals Profile Butadiene. Chemical and Engineering News. November 19, 19. 1979. Key Chemicals Profile Butadiene. VRD 0002037226 90 8. REFERENCES Chemical and Engineering News. November 17, 18. 1980. Key Chemicals Profile Butadiene. Chemical and Engineering News. November 30, 14. if 1981. Key Chemicals Profile Butadiene. Chemical and Engineering News . November 22, 21. 1982. Key Chemicals Profile Butadiene. Chemical and Engineering News. October 24, 15. 1983. Key Chemicals Profile Butadiene. Chemical and Engineering News . March 25, 25. 1985. Key Chemicals Profile Butadiene. Chemical and Engineering News. 9, 15. 1986. Key Chemicals Profile Butadiene. June Chemical Marketing Reporter. 17, 54. 1980. Chemical Profile: 1,3-Butadiene. March Chemical Marketing Reporter. 11, 56-58 1988. Chemical Profile: 1,3-Butadiene. April Chemline, 1989. National Library of Medicine Chemline [Database], September 5, 1989. CLPSD. 1989. Contract Laboratory Program Statistical Database. Company, Alexandria, VA. June 12, 1989. , Viar and CMA. 1991. Written communication (February 15) on the draft toxicological profile for butadiene. Association, Washington, D.C. to ATSDR regarding comments Chemical Manufacturers Cote IL and Bayard SP. 1990. Cancer risk assessment of 1,3-butadiene. Environ Health Perspect 86:149-153. Crouch CN, Pullinger DH, Gaunt IF. 1979. Inhalation toxicity studies with 1,3-butadiene:2. 3 Month toxicity study in rats. Am Ind Hyg Assoc J 40(9):796-802. Cunningham MJ, Choy WN, Arce GT, et al. 1986. In vivo sister chromatid exchange and micronucleus induction studies with 1,3-butadiene in B6C3F! mice and Sprague-Dawley rats. Mutagenesis 1(6):449-452. VRD 0002037227 91 8. REFERENCES Dahl AR, Bechtold WE, Bond JA, et al. n.d. Species differences in the metabolism and disposition of inhaled 1,3-butadiene and isoprene. Inhalation Toxicology Research Institute, Lovelace Biomedical and Environmental Research Institute, Albuquerque, NM. (unpublished study.] *Dahl AR, Bechtold WE, Bond JA, et al. 1990. Species differences in the metabolism and disposition of inhaled 1,3-butadiene and isoprene. Environ Health Perspect 86:65-69. *Dahl AR, Sun JD, Birnbaum LS, et al. 1991. Toxicokinetics of inhaled 1,3-butadiene in monkeys: comparison to toxicokinetics in rats and mice. Toxicol Appl Pharmacol 110:9-19. *Darnall KR, Lloyd AC, Winer AM, et al. 1976. Reactivity scale for atmospheric hydrocarbons based on reaction with hydroxyl radicals. Environ Sci Techno1 10:692-696. *Daubert TE, Danner RP. 1985. Data compilation tables of properties of pure compounds. American Institute of Chemical Engineers, 450. *Debont JAM, Attwood MM, Primrose SB. 1979. Epoxidation of short-chain alkenes in mycobacterium E20: The involvement of a specific mono-oxygenase. FEMS Microbiol Lett 6:183-188. *de Meester C. 1988. Genotoxic properties of 1,3-Butadiene. 195(104);273-281. Mutat Res *de Meester C, Poncelet F, Roberfroid M, et al. 1978. Mutagenicity of butadiene and butadiene monoxide. Biochem Biophys Res Commun 80:298-305. *de Meester C, Poncelet F, Roberfroid M, et al. 1980. The mutagenicity of butadiene towards Salmonella tvphimurium. Toxicol Lett 6:125-130. *Deutschmann S, Laib RJ, 1989. Concentration-dependent depletion of non-protein sulfhydryl (NPSH) content in lung, heart and liver tissue of rats and mice after acute inhalation exposure to butadiene. Toxicol Lett 45(23):175-183. *Dimitrades B, Sturm GP, Wesson TC, et al. 1975. Development and utility of reactivity scales from smog chamber data. RI 8023. Pittsburgh, PA: U.S. Bureau of Mines. *Divine BJ. 1989. An update on mortality among workers at a butadiene facility - preliminary results. Report by Texaco Inc., Houston, TX.* *Divine BJ. 1990. An update on mortality among workers at a 1,3-butadiene facility - preliminary results. Environ Health Perspect 86:119-128. VRD 0002037228 92 8. REFERENCES *Downs TD, Crane MW, Kim KU. 1987. Mortality among workers at a butadiene facility. Am J Ind Med 12(3):311-329. Duverger M, Lambotte M, Malvoisin E, et al. 1981. Metabolic activation and mutagenicity of 4 vinylic monomers (vinyl chloride, styrene, acrylonitrile, butadiene). Toxicol Eur Res 3(3):131-140. *Eisenreich SJ, Looney BB, Thornton JD. 1981. Airborne organic contaminants in the Great Lakes Ecosystem. Env Sci Tech 15:30-38. *Ellenhorn MJ, Barceloux DG. 1988. Medical toxicology: Diagnosis and treatment of human poisoning. Amsterdam: Elsevier Biomedical Press BV, *EPA. 1978. U.S. Environmental Protection Agency. Interim primary drinking water regulations. Federal Register 43:29135-29150. EPA. 1981a. Chemical hazard information profile draft report. 1,3-Butadiene. Washington, D.C.: Office of Toxic Substances, Office of Pesticides and Toxic Substances, U.S. Environmental Protection Agency. EPA. 1981b. Health and environmental effects profile on 1,3-butadiene. Cincinnati, OH: Environmental Criteria and Assessment Office. *EPA. 1982. Environmental Protection Agency. Methods for organic chemical analysis of municipal and industrial wastewater. Cincinnati, OH: Environmental Monitoring and Support Laboratory. EPA 600/14-82-057. EPA. 1984. Hepatocyte primary culture/DNA repair test of butadiene feedstock. Houston, TX: Gulf Oil Chemicals Company. *EPA. 1985a. Mutagenicity and carcinogenicity assessment of 1,3-butadiene. Washington, D.C.: Office of Health and Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency. EPA-600/8-85-004 F. *EPA. 1985b. Assessment of 1,3-butadiene as a potentially toxic air pollutant. Federal Register 50(197):41466. EPA. 1985c. Results from phase I of ongoing multi-phased research program on 1,3-butadiene. Washington, D.C.: Chemical Manufacturers Association. *EPA. 1986. Environmental Protection Agency. Methods for the determination of organic compounds in finished drinking water and raw source water. Cincinnati, OH: Physical and Chemical Methods Branch.* *EPA. 1987. Extremely hazardous substances list and threshold planning quantities; Emergency planning and release notification requirements. Federal Register 52(77):13378-13410. VRD 0002031229 93 8. REFERENCES *EPA. 1988a. Environmental Protection Agency. Guidelines establishing test procedures for the analysis of pollutants. 40 CFR 1:36, 249*267. *EPA 1988b. Environmental Protection Agency. 40 (part 355):182-191. Protection of environment. CFR *EPA. 1989a. Interim methods for development of inhalation reference doses. U.S. Environmental Protection Agency, Office of Health and Environmental Assessment. Washington, DC. EPA 600/8-88-066F. *EPA. 1989b. Environmental Protection Agency. data base: 106-99-0, 1,3-butadiene. Coordinated list of chemicals EPA. 1989c. Health and environmental effects document for 1,3-butadiene. Cincinnati, OH: Environmental Criteria and Assessment Office, Office of Health and Environmental Assessment, U.S. Environmental Protection Agency. Esmen N. 1979. 40:58*65. Retrospective industrial hygiene surveys. Am Ind Hyg Assoc J Ewing BB, Chian ESK, Cook JC, et al. 1977. Monitoring to detect previously unrecognized pollutants in surface waters - Appendix: Organic analysis data. Washington, DC: U.S. Environmental Protection Agency. EPA 560/6-77-015. Appendix: EPA 560/6-77-015A. Farley FF. 1977. Photochemical reactivity classification of hydrocarbons and other organic compounds. In: Dimitriades B, ed. Inter Conf Photochemical Oxidant Pollut Control. Research Triangle Park, NC: U.S. Environmental Protection Agency, 713-727. EPA 600/3-77-001B. Fasen JM, Roberts DR, Ungers LJ, et al. 1990. Occupational exposure of workers to 1,3-butadiene. Environ Health Perspec 86:11-18. Filser JG, Bolt HM. 1984. Inhalation pharmacokinetics based on gas uptake studies. VI. Comparative evaluation of ethylene oxide and butadiene monoxide as exhaled reactive metabolites of ethylene and 1,3-butadiene in rats. Arch Toxicol 55(4):219-223. Fox AJ, Lindars DC, Owen R. 1974. A survey of occupational cancer in the rubber and cablemaking industries: Results of five-year analysis, 1967-71. Br J Ind Med 31:140-151. Gaffney JS, Levine SZ. 1979. Predicting gas phase organic molecule reaction rates using linear free-energy correlations. I. Oxygen 0(3P) and hydroxyl addition and abstraction reactions. Int J Chem Kinet 11:1197-1209. vrd s e e n u n n 94 8. REFERENCES *Gay BW Jr, Bufalini JJ. 1971. Nitric acid and the nitrogen balance of irradiated hydrocarbons in the presence of oxides of nitrogen. Environ Sci Technol 5:422-425. Gibson JE, Starr TB. 1988. Opportunities for improving techniques for interspecies extrapolation in the risk assessment process. Environ Health Perspect 77:99-105. Gold LS, Stone TH, Bernstein L. 1989. Summary of carcinogenic potency and positivity for 492 rodent carcinogens in the carcinogenic potency database. Environ Health Perspect 79:259-272. *Graedel TE, Hawkins DT, Clayton LD. 1986. Atmospheric chemical compounds, sources, occurrence and bioassay. New York, NY: Academic Press, 144, 511, 587-588, 599, 605, 619. Guesten H, Filby WG, Schoof S. 1981. Prediction of hydroxyl radical reaction rates with organic compounds in the gas phase. Atmos Environ 15:1763-1765. *Guicherit R, Schulting FL. 1985. The occurrence of organic chemicals in the atmosphere of the Netherlands. Sci Total Environ 43:193-219. *Hackett PL, Sikov MR, Mast TJ, et al. 1987a. Inhalation developmental toxicology studies of 1,3-butadiene in the rat: Final report. Report to the National Institute of Environmental Health Sciences, National Toxicology Program by Pacific Northwest Laboratory, Richland, WA. ISS PNL-6414; DE88004186. *Hackett PL, Sikov MR, Mast TJ, et al. 1987b. Inhalation developmental toxicology studies: Teratology study of 1,3-butadiene in mice. National Toxicology Program PNL-6412. *Hackett PL, McClanahan BJ, Brown MG, et al. 1988a. Sperm-head morphology study in B6C3F1 mice following inhalation exposure to 1,3-butadiene: final technical report. Report to National Institute of Environmental Health Sciences, National Toxicology Program by Pacific Northwest Laboratory, Richland, WA. PNL-6459; DE88008620. *Hackett PL, Mast TJ, Brown MG, et al. 1988b. Dominant lethal study in CD-I mice following inhalation exposure to 1,3-butadiene: final technical report. ISS PNL-6545; DE88010185. Hampson RF. 1980. Chemical kinetic and photochemical data sheets for atmospheric reactions. Washington, DC: U.S. Department of Transportation. FAA-EE-80-17, Hampson RF Jr, Garvin D. 1977. atmospheric chemistry-1977. Reaction rate and photochemical data for 95 8. REFERENCES Harm RW Jr, Jensen PA. 1977. Water quality characteristics of hazardous materials. Texas A & M University: College Station Environmental Engineering Division. *Hansch C, Leo AJ. Pomona College. 1985. Medchem project. Issue No. 26. Claremont, CA: Hattis D, Wasson J. 1987. Pharmacokinetic/mechanism-based analysis of the carcinogenic risk of butadiene. Report to National Institute for Occupational Safety and Health, Rockville, MD, by Massachusetts Institute of Technology, Cambridge, MA. NTIS PB88-202817. *Hayano S, Jang HL, Furuya K, et al. 1985. Formation of hazardous substances and mutagenicity of PAH produced during the combustion process in a diesel engine. Atmos Environ 19:1009-1015. *Hendricks WD, Schultz GR. 1986. A sampling and analytical method for monitoring low ppm air concentrations of 1,3-butadiene. Appl Ind Hyg 4:186190. *Heuss JM, Glasson WA. 1968. Hydrocarbon reactivity and eye irritation. Environ Sci Technol 2:1109-1116. *Hine J, Mookerjee PK. 1975. The intrinsic hydrophilic character of organic compounds. Correlations in terms of structural contributions. J Org Chem 40:292-298. Hodson J. 1988. The estimation of the photodegradation of organic compounds by hydroxyl radical reaction rate constants obtained from nuclear magnetic resonance spectroscopy chemical shift data. Chemosphere 17:2339-2348. *Hou CT, Patel R, Laskin AI, et al. 1979, Microbial oxidation of gaseous hydrocarbons: Epoxidation of C2 to CA n-alkenes by methylotrophic bacteria. Appl Environ Microbiol 38:127-134. *Hou CT, Patel RN, Laskin AI, et al. 1980. Microbial oxidation of gaseous hydrocarbons: Oxidation of lower n-alenes and n-alkanes by resting cell suspensions of various methylotrophic bacteria, and the effect of methane metabolites. FEMS Microbiol Lett 9:267-270. *Hou CT, Patel R, Laskin AI, et al. 1983. Epoxidation of short-chain alkenes by resting-cell suspensions of propane-grown bacteria. Appl Environ Microbiol 46:171-177. *HSDB. 1989. Hazardous Substance Data Bank [Database]. Medicine. September 8, 1989. National Library of 000203 72 31 Z*S C3 VRD 8002037232 96 8. REFERENCES *Huff JE, Melnick RL, Solleveld HA, et al. 1985. Multiple organ carcinogenicity of 1,3-butadiene in B6C3FJ mice after 60 weeks of inhalation exposure. Science.227(4686):548-549. Hughes TW, Tierney DR, Khan ZS. 1987. Measuring fugitive emissions from petrochemical plants. Chem Eng Prog 75:35-39. IARC. 1986. IARC monographs on the evaluation of carcinogenic risk of chemicals to humans. Vol. 39: 1,3-Butadiene. World Health Organization, Lyon, France, 155-179. *IARC. 1987. IARC monographs on the evaluation of carcinogenic risks to humans. Supplement 7: Overall evaluations of carcinogenicity: An updating of IARC monographs volumes 1-42. World Health Organization, Lyon, France, 136137. Illing HPA, Shillaker R0. 1985. 1,3-Butadiene and related compounds. London, United Kingdom: H.M. Stationery Office. *IRIS. 1991. Integrated Risk Information System. U.S. Environmental Protection Agency, Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH. December 5, 1991. Irons RD. 1988. Studies on the mechanisms of chemically induced leukemia/lymphoma. CUT Activities 8(l):2-8. Irons RD. 1989. Studies on the mechanism of butadiene-induced leukemogenesis: The potential role of endogenous murine leukemia virus. Chemical Industry Institute of Toxicology, Research Triangle Park, NC. Irons RD, Smith CN, Stillman WS, et al. 1986a. Macrocytic-megaloblastic anemia in male B6C3F1 mice following chronic exposure to 1,3-butadiene. Toxicol Appl Pharmacol 83(1):95-100. Irons RD, Smith CN, Stillman WS, et al. 1986b. Macrocytic-megaloblastic anemia in male NIH Swiss mice following repeated exposure to 1,3-butadiene. Toxicol Appl Pharmacol 85(3):450-455. *Irons RD, Stillman WS, Cloyd MW. 1987a. Selective activation of endogenous ecotropic retrovirus in hematopoietic tissues of B6C3F1 mice during the preleukemic phase of 1,3-butadiene exposure. Virology 161(2):457-462. Irons RD, Oshimura M, Barrett JC. 1987b. Chromosome aberrations in mouse bone marrow cells following in vivo exposure to 1,3-butadiene. Carcinogenesis (Lond) 8(11):1711-1714. H IL IB 1 8 8 8 GHA 97 8. REFERENCES *Irons RD, Cathro HP, Stillman WS, et al. 1989. Susceptibility to 1,3-butadiene-induced leukemogenesis correlates with endogenous ecotropic retroviral background in the mouse. Toxicol Appl Pharmacol 101:170-176. *Irvine LFH. 1981. 1,3-Butadiene: Inhalation teratogenicity study in the rat: final report. Harrogate, England: Hazleton Laboratories Europe Ltd. OTS Submission, Microfiche No. 050 545. Jaber HM, Mabey WR, Liv AT, et al. 1984. Data acquisition for environmental transport and fate screening. Menlo Park, CA: SRI International, 312 p. EPA 600/6-84-009. NTIS PB84-243906. *Japar SM, Wu CH, Niki H. 1974. Rate constants for the reaction of ozone with olefins in the gas phase. J Phys Chem 78:2318-2320. *Jauhar PP, Henika PR, Macgregor JT, et al. 1988. 1,3-Butadiene: Induction of micronucleated erythrocytes in the peripheral blood of B6C3F! mice exposed by inhalation for 13 weeks. Mutat Res 209(3-4):171-176. *Jellito B, Vangala RR, Laib RJ. 1989. Species differences in DNA damage by butadiene: role of diepoxybutane. Arch Toxicol Suppl 13:246-249. *Jones B, Harris RL. 1983. Calculation of time-weighted average concentrations: A computer mapping application. Am Ind Hyg Assoc J 44:795801. *Junk GA, Ford CS. 1980. A review of organic emissions from selected combustion processes. Chemosphere 9:187-230. Katzman H, Libby WF. 1975. Hydrocarbon emissions from jet engines operated at simulated high-altitude supersonic flight conditions. Atmos Environ 9:839842. *Kirshenbaum I. 1978. Butadiene. In: Stannden A, ed. Kirk-Othmer encyclopedia of chemical technology, Vol, 4, 3rd ed. New York, NY: John Wiley and Sons, Inc., 313-337. *Kopczynski SL, Lonneman WA, Sutterfield FD, et al. 1972. Photochemistry of atmospheric samples in Los Angeles. Environ Sci Technol 6:342-347. Korth MW. 1963. Dynamic irradiation chamber tests of automotive exhaust. Cincinnati, OH: U.S. Department of Health, Education, and Welfare. U.S. DHEW-999-AP-5.* *Kraybill HF. 1980, Evaluation of public health aspects of carcinogenic/ mutagenic biorefractories in drinking water. Prev Med 9:212-218. VRD 0002037234 98 8. REFERENCES *Kreiling R, Laib RJ, Bolt HM. 1986a. Alkylation of nuclear proteins and DNA after exposure of rats and mice to carbon-14 1,3-butadiene. Toxicol Lett (Amst) 30(2):131-I36. *Kreiling R, Laib RJ, Filser JG, et al. 1986b. Species differences in butadiene metabolism between mice and rats evaluated by inhalation pharmacokinetics. Arch Toxicol 58(4):235-238. Kreiling R, Laib RJ, Filser JG, et al. 1987. Inhalation pharmacokinetics of 1.2- epoxybutene-3 reveal species differences between rats and mice sensitive to butadiene-induced carcinogenesis. Arch Toxicol 61(1):7-11. Kreiling R, Laib RF, Bolt HM. 1988. Depletion of hepatic non-protein sulfhydryl content during exposure of rats and mice to butadiene. Toxicol Lett 41(3):209-214. Laib RJ, Kreiling R, Vangala RR. 1987. Analysis of DNA-interactions of carcinogenic xenobiotics: A way to evaluate the reactive principles in metabolism and toxicity. J Cancer Res Clin Oncol 113:S18. Laib RJ, Filser JG, Kreiling R. 1988. Species differences in butadiene metabolism between mouse and rat. Ann NY Acad Sci 534:663-670. Laib RJ, Filser JG, Kreiling R. 1990. Inhalation pharmacokinetics of 1.3- butadiene and 1,2 - epoxybutene-3 in rats and mice. Environ Health Perspect 86: 57-63. Leiderman LJ, Stillman WS, Shah RS, et al. 1986. Altered hematopoietic stem cell development in male B6C3Fi mice following exposure to 1,3-butadiene. Exp Molecul Path 44(l):50-56. Linet MS, Stewart WF, Van Natta ML, et al. 1987. Comparison of methods for determining occupational exposure in a case-control interview study of chronic lymphocytic leukemia. J Occup Med 29(2):136-141. Lloyd AC, Darnall KR, Winer AM, et al. 1976. Relative rate constants for reaction of the hydroxyl radical with series of alkanes, alkenes, and aromatic hydrocarbons. J Phys Chem 80:789-794. Loeser E. 1985. European research activities on butadiene. Int Inst Synth Rubber Prod 26(11-2). Ann Meet Proc *Lofroth G, Burton RM, Forehand L, et al. 1989. Characterization of environmental tobacco smoke. Environ Sci Technol 23:610-614.* *Lonneman WA, Namie GR, Bufalini JJ, 1979. Hydrocarbons in Houston air. Research Triangle Park, NC: U.S. Environmental Protection Agency. EPA 600/3-79-018, 36. VRD 0002037235" 99 8. REFERENCES Loprieno N, Prescluttini S, Sbrana I, et al. 1978. Mutagenicity of industrial compounds. VII. Styrene and styrene oxide: II. Point mutations, chromosomes aberrations and DNA repair induction analyses. Scand J Work Environ Health 4:169-178. Louw CW, Richards JF, Faure PK. 1977. The determination of volatile organic compounds in city air by gas chromatography combined with standard addition, selective substraction, infrared spectrometry and mass spectrometry. Atmos Environ 11:703-717. Lunsford RA. 1987. Comments on sampling and analytical method for monitoring low-ppm air concentrations of 1,3-butadiene. Appl Ind Hyg 2:93-94. Lunsford RA, Gagnon YT. 1987. Use of a back-flushable pre-column to maintain the performance of an aluminium oxide porous-layer open-tubular fused silica column for the determination of 1,3-butadiene in air. Journal of High Resolution Chromatography and Chromatography Communication 10:102-104. Lyman WJ, Reehl WF, Rosenblatt DH. 1982. Handbook of chemical property estimation methods. New York, NY: McGraw Hill Book Co. Chapters 4, 5 and 15. Maldotti A, Chiorboli C, Bignozzi CA, et al. 1980. Photoxidation of 1.3- butadiene containing systems: Rate constant determination for the reaction of acrolein with -OH radicals. Int J Chem Kinet 12:905-913. Malvoisin E, Lhoest G, Poncelet F, et al. 1979. Identification and quantitation of 1,2-epoxybutene-3 as the primary metabolite of 1,3-butadiene. J Chromatog 178(2):419-425. Malvoisin E, Roberfroid M. 1982. Hepatic microsomal metabolism of 1.3-butadiene. Xenobiotica 12(2):137-144. Maronpot RR. 1987. Ovarian toxicity and carcinogenicity in eight recent national toxicology program studies. Environ Health Perspec 73:125-130. Matanoski G, Schwartz L. 1987. Mortality of workers in styrene-butadiene polymer production. J. Occup Med 29:675-680. Matanoski GM, Schwartz L, Sperrazza J, et al. 1982. Mortality of workers in the styrene-butadiene rubber polymer manufacturing industry. Baltimore, MD: Johns Hopkins University School of Hygiene and Public Health. Matanoski GM, Santos-Burgoa C, Schwartz L. 1988. Mortality of a cohort of workers in the styrene-butadiene polymer manufacturing industry 1943-1982. (final report prepared under contract to International Institute of Synthetic Rubber Producers, Inc.). The Johns Hopkins University, School of Hygiene and Public Health, Baltimore, Maryland. VRD 0002037236 100 8. REFERENCES Matanoski Gtt, Santos-Burgoa C, Zeger SL, et al. 1989a. Epidemiologic data related to health effects of 1,3-butadiene. In: Mohn U, ed. Assessment of inhalation hazards: Integration and extrapolation using diverse data. New York, NY: Springer-Verlag, 201-214. *Matanoski GH, Santos-Burgoa C, Zeger SL, et al. 1989b. Nested case-control study of lymphopoietic cancers in workers in the styrene-butadiene polymer manufacturing industry (final report prepared under contract to International Institute of Synthetic Rubber Producers, Inc.). The Johns Hopkins University, School of Hygiene and Public Health, Baltimore, Maryland. *MCA. 1974. Chemical safety data sheet SD-55. Properties and essential information for safe handling and use of butadiene. Washington, DC: Manufacturing Chem Assoc. *McAuliffe C. 1966. Solubility in water of paraffin, cycloparaffin, olefin, acetylene, cycloolefin and aromatic hydrocarbons. J Phys Chem 70:1267-1275. *McMichael AJ, Spirtas R, Kupper LL. 1974. An epidemiologic study of mortality within a cohort of rubber workers, 1964-1972. J Occup Med 16:458464. *McMichael AJ, Spirtas R, Kupper LL, et al. 1975. Solvent exposure and leukemia among rubber workers: An epidemiologic study. J Occup Med 17:234239. *McMichael AJ, Spirtas R, Gamble JF, et al. 1976. Mortality among rubber workers. Relationship to specific jobs. J Occup Med 18(3):178-185. *McNeal TP, Breder CV. 1987. Headspace gas chromatographic determination of residual 1,3-butadiene in rubber-modified plastics and its migration from plastic containers into selected foods. J Assoc Off Anal Chem 70:18-21. Meinhardt TJ, Young RJ, Hartle RW. 1978. Epidemiologic investigations of styrene-butadiene rubber production and reinforced plastics production. Scand J Work Environ Health 4:240-246. *Meinhardt TJ, Lemen RA, Crandall MS, et al. 1982. Environmental epidemiologic investigation of the styrene-butadiene rubber industry. Work Environ Health 8:250-259. Scand J Melnick RL, Huff JE, Haseman JK, et al. 1988. Chronic toxicity results and ongoing studies of 1,3-butadiene by the National Toxicology Program. Ann N Y Acad Sci 534:648-662. VRD 8882037237 101 8. REFERENCES *Melnick R, Huff J, Miller R. 1989. Toxicology and carcinogenicity of 1.3- butadiene. In; Mohn TJ, ed. Assessment of inhalation hazards: Integration and extrapolation using diverse data. New York, NY: SpringerVerlag, 177-188. Melnick RL, Huff JE, Bird MG, et al. 1990. Symposium overview: Toxicology, carcinogenesis, and human health aspects of 1,3-butadiene. Environ Health Perspect 86:3-5. *Melnick RL, Huff JE, Roycroft JH, et al. 1990. Inhalation toxicology and carcinogenicity of 1,3-butadiene in B6C3F1 mice following 65 weeks of exposure. Environ Health Perspect 86:27-36. *Miller LM. 1978. Investigation of selected potential environmental contaminants: Butadiene and its oligomers. Philadelphia, PA: Franklin Research Center. EPA 560/2-78-008. *Miller RA, Boorman GA. 1989. Morphology of neoplastic lesions induced by 1.3- butadiene in B6C3F1 mice. Prepared by Battelle Pacific Northwest Laboratories, Richland, Washington, for National Toxicology Program, Research Triangle Park, NC. *Mulcahy MFR, Nelson PF, Smith MY, et al. 1976. Smog forming hydrocarbons In urban air. In: Proc. Syrap. Workshop Session: Occurrence Control Photochem Pollut. Paper No. IV. *Mullins JA. 1990. Perspec 86:9-10. Industrial emissions of 1,3-butadiene. Environ Health *NAS/NRC. 1989. Biologic markers in reproductive toxicology. National Academy of Sciences/National Research Council. Washington, DC: National Academy Press, 15-35. *NATICH. 1988. National Air Toxics Information Clearinghouse. Database report of state, local and EPA air toxics activities. Office of Air Quality Planning and Standards, U.S. Environmental Protection Agency, Research Triangle Park, NC. *Neligan RE. 1962. Health. 5:581-591. Hydrocarbons in the Los Angeles atmosphere. Arch Environ *Niki H, Maker PD, Savage CM, et al. 1983. Atmospheric ozone-olefin reactions. Environ Sci Technol 17:312A-322A. NIOSH. 1976. Proceedings of NIOSH styrene-butadiene briefing. OH: U.S. DHEW. NTIS PB77-129. Cincinnati, VRI) 008 20 3 72 3 8 102 8. REFERENCES *NIQSH. 1987. NIOSH manual of analytical methods, 3rd ed, 2nd supp. Cincinnati, OH: U.S. Department of Health and Human Services, Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Publication No. 87-117. *NI0SH. 1988. NIOSH recommendations for safety and health standards. Cincinnati, OH: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Institute for Occupational Safety and Health. *NI0SH. 1989. National Occupational Exposure Survey (NOES). Cincinnati, U.S. Department of Health and Human Services, Centers for Disease Control, National Institute for Occupational Safety and Health. OH: *Nip WS, Singleton DL, Cvetanovic RJ. 1979. Temperature dependence of rate constants for reaction of oxygen atoms, 0(3P) with allene and 1,3-butadiene. Can J Chem 57:949-952. *Norppa H, Sorsa M, Vainio H. 1980. Chromosomal aberrations in bone marrow of Chinese hamsters exposed to styrene and ethanol. Toxicol Lett 5:241-244. *NTP. 1984. NTP technical report on the toxicology and carcinogenesis studies of 1,3-butadiene in B6C3F1 mice. National Toxicology Program. Research Triangle Park, NC. NTP TR 288. NTP-83-071. NIH Pub. No. 84-2544. *NTP. 1991. National Toxicology Program--technical report series no. 434. Toxicology and carcinogenesis studies of 1,3-butadiene (CAS No. 106-99-0) in B6C3F1 mice (inhalation studies). Board Draft, Research Triangle Park, NC: U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health. NIH publication no. 92-3165. *0SHA. 1989. U.S. Department of Labor. Occupational Safety and Health Administration. Air contaminants. Final rule. Federal Register 54(12):2926. *0SHA. 1990. U.S. Department of Labor. Occupational Safety and Health Administration. Occupational exposure to 1,3-butadiene. Proposed rule. Federal Register 55 (155):32736 *Owen PE, Glaister JR, Gaunt IF, et al. 1987. Inhalation toxicity studies with 1,3-butadiene: 3. two year toxicity/carcinogenicity study in rats. Am Ind Hyg Assoc J 48(5):407-413. ^Pacific Environmental Services, Inc. 1987. Toxic air pollutant/source crosswalk-a screening tool for locating possible sources emitting toxic air pollutants. Washington, DC: U.S. Environmental Protection Agency. EPA 450/4-87-023A. VRD 000203 T2 39 103 8. REFERENCES Parsons TB, Wilkins GE. 1976. Biological effects and environmental aspects of 1,3-butadiene. U.S. EPA Contract 68-01-3249, NTIS PB-253 982. *Patel RN, Hou CT, Laskin AI, et al. 1979. Microbial oxidation of gaseous hydrocarbons. II. Hydroxylation of alkanes and epoxidation of alkenes by cell-free particulate fractions of methane-utilizing bacteria. J. Bacterid 139:675-679. *Patel RN, Hou CT, Laskin AI. 1982a. Oxidation of gaseous hydrocarbons and related compounds by methanotrophic organisms. In: Developments in industrial microbiology, Vol. 23, 187-205. *Patel RN, Hou CR, Laskin AI, et al. 1982b. Microbial oxidation of hydrocarbons: Properties of a soluble methane monoxygenase from a facultative methane utilizing organism Methlobacterium sp. Strain CRL-26. Appl Environ Microbiol 44:1130-1137. Pohlova H, Rossner P, Sram RJ. 1985. Cytogenetic analysis of human peripheral blood lymphocytes in culture exposed in vitro to styrene and styrene oxide. J Hyg Epidem Microbiol Immunol 29:269-274. Poncelet F, De Meester C, Duverger-van Bogaert M, et al. 1980. Influence of experimental factors on the mutagenicity of vinyl monomers. Arch Toxicol 4:63-66. Reinhardt CF. 1987. Meeting new challenges in industrial toxicology. J Toxicol Sci 12(2):235-241. *Rigby LJ. 1981. The collection and identification of toxic volatiles from plastics under thermal stress. Ann Occup Hyg 24:331-346. Rosenthal SL, 1985. The reproductive effects assessment group's report on the mutagenicity of 1,3-butadiene and its reactive metabolites. 7(6):933-945. Environ Mutagen *Sabourin PJ, Burka LT, Dahl AR, et al. 1991. Species differences in metabolism of inhaled butadiene [Abstract], Toxicologist 11(1):88. *Sandmeyer EE. 1981. Aliphatic hydrocarbons: Butadiene. In: Clayton GD, Clayton FE, ed. Patty's industrial hygiene and toxicology, 3rd revised ed. New York, NY: John Wiley and Sons, Vol. 2B. *SANSS. 1989. Structure and Nomenclature Search System [Database], September 5, 1989. Santodonato J, Bosch S, Meylan W, et al. 1985. Monograph on human exposure to chemicals in the workplace: 1,3-Butadiene. Report to National Toxicology Program by Syracuse Research Corporation, Syracuse, NY. VRD 0002037240 104 8. REFERENCES *Sax NI, Lewis RJ. 1987. Hawley's condensed chemical dictionary, 11th ed. New York, NY: Van Nostrand Reinhold Co, 177. Schmidt U, Loeser E. 1985. Species differences in the formation of butadiene monoxide from 1,3-butadiene. Arch Toxicol 57:222-225. Schmidt U, Loeser E. 1986. Epoxidation of 1,3-butadiene in liver and lung tissue of mouse, rat, monkey and man. Adv Exp Med Biol 197:951-957. Seila RL, Arnsts RR, Buchanan, JW. 1984. Atmospheric volatile hydrocarbon composition at five remote sites in northwestern North Carolina. Research Triangle Park, NC: U.S. Environmental Protection Agency. EPA 600/D-84-092. NTIS PB84-117930. Serenbetz H. 1983. Review of 1,3-butadiene, the workplace, and regulatory considerations. Rubber Prod 24(6):1-25. its toxicity profile, risk in Ann Meet Proc Int Inst Synth Shah JJ, Heyerdahl EK. (VOCS) database update. 1988. National ambient volatile organic compound EPA 600/3-88-010, 54. Sharief Y, Brown AM, Backer LC, et al. 1986. Sister chromatid exchange and chromosome aberration analyses in mice after in vivo exposure to acrylonitrile, styrene, or butadiene monoxide. Environ Mutagen 8:439-448. Shugaev BB, Yaroslavl BS. 1969. Concentrations of hydrocarbons in tissues as a measure of toxicity. Arch Environ Health 18:878-882. Sigsby JE Jr, Tejada S, Ray W, et al. 1987. Volatile organic compound emissions from 46 in-use passenger cars. Environ Sci Technol 21:466-475. Singh HB, Jaber HM, Davenport JE. 1984. Reactivity/volatility classification of selected organic chemicals: Existing data. Menlo Park, CA: SRI International. EPA 600/3-84-082. NTIS PB85-232883. Solleveld HA, Miller RA, Banas DA, et al. 1988. Primary cardiac hemangiosarcomas induced by 1,3-butadiene in B6C3F1 hybrid mice. Toxicol Pathol 16(1):46-52. SRI. 1991. 1991 Directory of Chemical Producers, U.S.A, Stanford Research Institute, 503. Menlo Park, CA: Startin JR, Gilbert J. 1984. Single ion monitoring of butadiene in plastics and foods by coupled mass spectrometry - automatic head-space gas chromatography. J Chromatogr 294:427-430. State of Kentucky. 1986. New or modified sources emitting toxic air pollutants. Department for Environmental Protection. 401 KAR 63:022. 105 8. REFERENCES Steere NV, ed. 1968. Safety in the chemical laboratory. XLV1. Hazardous chemicals data. J Chem Educ 45(3):4199-4205. Stephens ER, Burleson FR. 1967. Analysis of the atmosphere for light hydrocarbons. J Air Pollut Control Assoc 17:147-153. Stephens ER, Burleson FR. 1969. Distribution of light hydrocarbons in ambient air. J Air Pollut Control Assoc 19:929-936. Stump FD, Dropkin DL. 1985. Gas chromatographic method for quantitative determination of C2 to C13 hydrocarbons in roadway vehicle emissions. Anal Chera 57:2629-2634. Stump F, Tejada S, Ray W, et al. 1989. The influence of ambient temperature on tailpipe emissions from 1984-1987 model year light-duty gasoline motor vehicles. Atmos Environ 23:307-320. Stutz and Janusz. 1988. Hazardous materials injuries (a handbook for pre hospital care). Beltsville, MD: Bradford Communication Corp, 300-301. Sun JD, Dahl AR, Bond JA, et al. 1989a. Metabolism of inhaled butadiene in monkeys: Comparison to rodents. Exp Pathol 37:133-135. Sun JD, Dahl AR, Bond JA, et al. 1989b. Characterization of hemoglobin adduct formation in mice and rats after administration of carbon-14 butadiene or carbon-14 isoprene. Toxicol Appl Pharmacol 100:86-95. Swann RL, Laskowski DA, McCall PJ, et al. 1983. A rapid method for the estimation of the environmental parameters octanol/water partition coefficient, soil sorption constant, water to air ratio, and water solubility. Res Rev 85:17-28. Texas Air Control Board, 1990. Written communication to Bill Henriques, Agency for Toxic Substances and Disease Registry, regarding 1,3-butadiene concentrations in air. Texas Air Control Board, Austin, TX. Thom NS, Agg AR. 1975, The breakdown of synthetic organic compounds in biological processes. Proc R Soc Lon B 189:347-357. Thurmond LM, Lauer LD, House RV, et al. 1986. Effect of short-term inhalation exposure to 1,3-butadiene on murine immune functions. Toxicol Appl Pharmacol 86(2):170-179. Tice RR. 1988. The cytogenetic evaluation of in vivo genotoxic and cytotoxic activity using rodent somatic cells. Cell Biol Toxicol 4(4):475-486. m iE D lflB fl 70 C3 I 106 8. REFERENCES *Tice RR, Boucher R, Luke CA, et al. 1987. Comparative cytogenetic analysis of bone marrow damage induced in male B6C3F! mice by multiple exposure to gaseous 1,3-butadiene. Environ Mutagen 9(3):235-250. *TRI. 1989. The toxics release inventory. National Library of Medicine, National Toxicology Information Program, Bethesda, MD. *Tumbull D, Rodricks JV, Brett SN. 1988. Assessment of the potential risk to workers from exposure to butadiene. ENVIRON Corporation, Washington, DC. *USITC. 1988. Publication No. 2-2 to 2-7. Synthetic organic chemicals: U.S. production and sales 1987. 2118. Washington, DC: U.S. International Trade Commission, *USITC. 1989. Publication No. 2-2 to 2-7. Synthetic organic chemicals: U.S. production and sales 1988. 2219. Washington, DC: U.S. International Trade Commission, *Van Duuren BL, Nelson N, Orris L, et al. 1963. Carcinogenicity of epoxides, lactones, and peroxy compounds. J Natl Cancer Inst 31:41-55. *VanGinkel CG, Welten HGJ, Debont JAM. 1987. Oxidation of gaseous and volatile hydrocarbons by selected alkene-utilizing bacteria. Appl Environ Microbiol 53:2903-2907. *Verschueren K. 1983. Handbook of environmental data on organic chemicals. New York, NY: Van Nostrand Reinhold Co., 296-297. *Victorin K, Stahlberg M. 1988. A method for studying the mutagenicity of some gaseous compounds in Salmonella tvphlmurium. Environ Mol Mutagen 11(1):65-77. *View Database. 1989. Agency for Toxic Substances and Disease Registry (ATSDR), Office of External Affairs, Exposure and Disease Registry Branch, Atlanta, GA. November 8, 1989. *Watabe T, Isobe M, Sawahata T, et al. 1978. Metabolism and mutagenicity of styrene. Scand J Work Environ Health 4(2):142-155. *Watkinson RJ, Somerville HJ. 1976. The microbial utilization of butadiene. In: 3rd Proc Int Biodegradation Symp, 1975, 35-42. *Weast RC, Astle MJ, Beyer WH. 1988. CRC handbook of chemistry and physics, 69th ed. Boca Raton, FL: CRC Press, Inc., C-161. Wilson RH. 1944. Health hazards encountered in the manufacture of synthetic rubber. J Am Med Assoc 124(11):701-703. IH L tU S U B (IMA 107 8. REFERENCES Wilson RH, McCormick WE. 1954. Toxicity of plastics and rubber, plastomers and monomers. Ind Med Surg 23:479. Windholz M, Budavari S, Blumetti RF, et al. NJ, Merck and Co., Inc, 209. 1983. The Merck Index. Rahway, Wooder MF. 1986. 1,3-Butadiene - an overview. Rubber Prod 27(111-5). Ann Meet Proc -Int Inst Synth Yanagihara S, Shimada I, Shinoyama E, et al. 1977. Photochemical reactivities of hydrocarbons. Proc 4th Int Clean Air Congr, 472-477.* *Zhou XT, Li LR, Cui MY, et al. 1986. Cytogenetic monitoring of petrochemical workers {Abstract]. Environ Mutagen 8(6):96. 30 VRD 00020372 4-4 109 - 9. GLOSSARY Acute Exposure -- Exposure to a chemical for a duration of 14 days or less, as specified in the Toxicological Profiles. Adsorption Coefficient (K^) -- The ratio of the amount of a chemical adsorbed per unit weight of organic carbon in the soil or sediment to the concentration of the chemical in solution at equilibrium. Adsorption Ratio (K^) -- The amount of a chemical adsorbed by a sediment or soil (i.e., the solid phase) divided by the amount of chemical in the solution phase, which is in equilibrium with the solid phase, at a fixed solid/solution ratio. It is generally expressed in micrograras of chemical sorbed per gram of soil or sediment. Bioconcentration Factor (BCF) -- The quotient of the concentration of a chemical in aquatic organisms at a specific time or during a discrete time period of exposure divided by the concentration in the surrounding water at the same time or during the same period. Cancer Effect Level (CEL) -- The lowest dose of chemical in a study, or group of studies, that produces significant increases in the incidence of cancer (or tumors) between the exposed population and its appropriate control. Carcinogen -- A chemical capable of inducing cancer. Ceiling Value -- A workplace concentration of a substance that should not be exceeded, even instantaneously. Chronic Exposure -- Exposure to a chemical for 365 days or more, as specified in the Toxicological Profiles. Developmental Toxicity -- The occurrence of adverse effects on the developing organism that may result from exposure to a chemical prior to conception (either parent), during prenatal development, or postnatally to the time of sexual maturation. Adverse developmental effects may be detected at any point in the life span of the organism. Embryotoxicity and Fetotoxicity -- Any toxic effect on the conceptus as a result of prenatal exposure to a chemical; the distinguishing feature between the two terms is the stage of development during which the insult occurred. The terms, as used here, include malformations and variations, altered growth, and in utero death. EPA Health Advisory --An estimate of acceptable drinking water levels for a chemical substance based on health effects information. A health advisory is not a legally enforceable federal standard, but serves as technical guidance to assist federal, state, and local officials. VRD 000 20 3 72 4-5 110 9. GLOSSARY Immediately Dangerous to Life or Health (IDLH) -- The maximum environmental concentration of a contaminant from which one could escape within 30 min without any escape-impairing symptoms or irreversible health effects. Intermediate Exposure -- Exposure to a chemical for a duration of 15-364 days as specified in the Toxicological Profiles. Immunologic Toxicity -- The occurrence of adverse effects on the immune system that may result from exposure to environmental agents such as chemicals. In Vitro -- Isolated from the living organism and artificially maintained, as in a test tube. In Vivo -- Occurring within the living organism. Lethal Concentration^) (LClq) -- The lowest concentration of a chemical in air which has been reported to have caused death in humans or animals. Lethal Concentration^) (LC50) - - A calculated concentration of a chemical In air to which exposure for a specific length of time is expected to cause death in 502 of a defined experimental animal population. Lethal Dose(I<0) (LDj^) -- The lowest dose of a chemical introduced by a route other than inhalation that is expected to have caused death in humans or animals. Lethal Dose(5Q) (LD50) The dose of a chemical which has been calculated to cause death in 50% of a defined experimental animal population. Lethal Timet50) (LT50) -- A calculated period of time within which a specific concentration of a chemical is expected to cause death in 502 of a defined experimental animal population. Lowest-Observed-Adverse-Effect Level (LOAEL) -- The lowest dose of chemical in a study, or group of studies, that produces statistically or biologically significant increases in frequency or severity of adverse effects between the exposed population and its appropriate control. Malformations -- Permanent structural changes that may adversely affect survival, development, or function. Minimal Risk Level --An estimate of daily human exposure to a chemical that is likely to be without an appreciable risk of deleterious effects (noncancerous) over a specified duration of exposure. 9. GLOSSARY Mutagen -- A substance that causes mutations. A mutation is a change in the genetic material in a body cell. Mutations can lead to birth defects, miscarriages, or cancer. Neurotoxicity -- The occurrence of adverse effects on the nervous system following exposure to chemical. No-Observed-Adverse-Effect Level (NOAEL) -- The dose of chemical at which there were no statistically or biologically significant Increases in frequency or severity of adverse effects seen between the exposed population and its appropriate control. Effects may be produced at this dose, but they are not considered to be adverse. Octanol-Water Partition Coefficient (K^,) -- The equilibrium ratio of the concentrations of a chemical in n-octanol and water, in dilute solution. Permissible Exposure Limit (PEL) -- An allowable exposure level in workplace air averaged over an 8-hour shift. Qi* -- The upper-bound estimate of the low-dose slope of the dose-response curve as determined by the multistage procedure. The qj* can be used to calculate an estimate of carcinogenic potency, the incremental excess cancer risk per unit of exposure (usually pg/L for water, mg/kg/day for food, and fMg/m3 for air) . Reference Dose (RfD) --An estimate (with uncertainty spanning perhaps an order of magnitude) of the daily exposure of the human population to a potential hazard that is likely to be without risk of deleterious effects during a lifetime. The RfD is operationally derived from the NOAEL (from animal and human studies) by a consistent application of uncertainty factors that reflect various types of data used to estimate RfDs and an additional modifying factor, which is based on a professional judgment of the entire database on the chemical. The RfDs are not applicable to nonthreshold effects such as cancer. Reportable Quantity (RQ) -- The quantity of a hazardous substance that is considered reportable under CERCLA. Reportable quantities are (1) 1 lb or greater or (2) for selected substances, an amount established by regulation either under CERCLA or under Sect. 311 of the Clean Water Act. Quantities are measured over a 24-hour period. Reproductive Toxicity -- The occurrence of adverse effects on the reproductive system that may result from exposure to a chemical. The toxicity may be directed to the reproductive organs and/or the related endocrine system. The manifestation of such toxicity may be noted as alterations in sexual behavior, fertility, pregnancy outcomes, or modifications in other functions that are dependent on the integrity of this system. VRD 0002037247 112 9. GLOSSARY Short-Term Exposure Limit (STEL) -- The maximum concentration to which workers can be exposed for up to 15 min continually. No more than four excursions are allowed per day, and there must be at least 60 min between exposure periods. The daily TLV-TWA may not be exceeded. Target Organ Toxicity -- This term covers a broad range of adverse effects on target organs or physiological systems (e.g., renal, cardiovascular) extending from those arising through a single limited exposure to those assumed over a lifetime of exposure to a chemical. Teratogen -- A chemical that causes structural defects that affect the development of an organism. Threshold Limit Value (TLV) -- A concentration of a substance to which most workers can be exposed without adverse effect. The TLV may be expressed as a TWA, as a STEL, or as a CL. Time-Weighted Average (TWA) -- An allowable exposure concentration averaged over a normal 8-hour workday or 40-hour workweek. Toxic Dose (TD50) -- A calculated dose of a chemical, introduced by a route other than inhalation, which is expected to cause a specific toxic effect in 50X of a defined experimental animal population. Uncertainty Factor (UF) -- A factor used in operationally deriving the RfD from experimental data. UFs are intended to account for (1) the variation in sensitivity among the members of the human population, (2) the uncertainty in extrapolating animal data to the case of human, (3) the uncertainty in extrapolating from data obtained in a study that is of less than lifetime exposure, and (4) the uncertainty in using LOAEL data rather than NOAEL data. Usually each of these factors is set equal to 10. VRD 0 0 0 2 0 *1 2 4 8 A-l APPENDIX A USER'S GUIDE Chapter 1 Public Health Statement This chapter of the profile is a health effects summary written in nontechnical language. Its intended audience is the general public especially people living in the vicinity of a hazardous waste site or substance release. If the Public Health Statement were removed from the rest of the document, it would still communicate to the lay public essential information about the substance. The major headings in the Public Health Statement are useful to find specific topics of concern. The topics are written in a question and answer format. The answer to each question includes a sentence that will direct the reader to chapters in the profile that will provide more information on the given topic. Chapter 2 Tables and Figures for Levels of Significant Exposure (LSE) Tables (2-1, 2-2, and 2-3) and figures (2-1 and 2-2) are used to summarize health effects by duration of exposure and endpoint and to illustrate graphically levels of exposure associated with those effects. All entries in these tables and figures represent studies that provide reliable, quantitative estimates of No-Observed-Adverse-Effect Levels (NOAELs), Lowest-Observed- Adverse-Effect Levels (LOAELs) for Less Serious and Serious health effects, or Cancer Effect Levels (CELs). In addition, these tables and figures illustrate differences in response by species, Minimal Risk Levels (MRLs) to humans for noncancer end points, and EPA's estimated range associated with an upper-bound individual lifetime cancer risk of 1 in 10,000 to 1 in 10,000,000. The LSE tables and figures can be used for a quick review of the health effects and to locate data for a specific exposure scenario. The LSE tables and figures should always be used in conjunction with the text. The legends presented below demonstrate the application of these tables and figures. A representative example of LSE Table 2-1 and Figure 2-1 are shown. The numbers in the left column of the legends correspond to the numbers in the example table and figure. LEGEND See LSE Table 2-1 (1). Route of Exposure One of the first considerations when reviewing the toxicity of a substance using these tables and figures should be the relevant and appropriate route of exposure. When sufficient data exist. VRD 0 0 0 2 0 3 7 2 0 A-2 APPENDIX A three LSE tables and two LSE figures are presented in the document. The three LSE tables present data on the three principal routes of exposure, i.e., inhalation, oral, and dermal (LSE Table 2-1, 2-2, and 2-3, respectively). LSE figures are limited to the inhalation (LSE Figure 2-1) and oral (LSE Figure 2-2) routes. (2) . Exposure Duration Three exposure periods: acute (14 days or less); intermediate (15 to 364 days); and chronic (365 days or more) are presented within each route of exposure. In this example, an inhalation study of intermediate duration exposure is reported. (3) . Health Effect The major categories of health effects included in LSE tables and figures are death, systemic, immunological, neurological, developmental, reproductive, and cancer. NOAELs and LOAELs can be reported in the tables and figures for all effects but cancer. Systemic effects are further defined in the "System'* column of the LSE table. (4) . Key to Figure Each key number in the LSE table links study information to one or more data points using the same key number in the corresponding LSE figure. In this example, the study represented by key number 18 has been used to define a NQAEL and a Less Serious LOAEL (also see the two N18r" data points in Figure 2-1). (5). Species The test species, whether animal or human, are identified in this column. (6). Exposure Frequency/Duration The duration of the study and the weekly and daily exposure regimen are provided in this column. This permits comparison of NOAELs and LOAELs from different studies. In this case (key number 18), rats were exposed to [substance x] via inhalation for 13 weeks, 5 days per week, for 6 hours per day. (7). System This column further defines the systemic effects. These systems include: respiratory, cardiovascular, gastrointestinal, hematological, musculoskeletal, hepatic, renal, and dermal/ocular. "Other" refers to any systemic effect (e.g., a decrease in body weight) not covered in these systems. In the example of key number 18, (respiratory) was investigated in this study. one systemic effect (8). NQAEL A No-Observed-Adverse-Effect Level (NOAEL) is the highest exposure level at which no harmful effects were seen in the organ system studied. Key number 18 reports a NOAEL of 3 ppm for the respiratory system which was used to derive an intermediate exposure, inhalation MRL of 0.005 ppm (see footnote "c"). (9). LOAEL A Lowest-Observed-Adverse-Effect Level (LOAEL) is the lowest exposure level used in the study that caused a harmful health effect. LOAELs have been classified into "Less Serious" and "Serious" effects. These distinctions help readers identify the levels of exposure at which adverse health effects first appear and the gradation of effects with increasing dose. A brief description of the specific end point used to VRD 0002037250 A-3 APPENDIX A quantify the adverse effect accompanies the LOAEL, The "Less Serious" respiratory effect reported in key number 18 (hyperplasia) occurred at a LQAEL of 10 ppm. (10) . Reference profile. The complete reference citation is given in Chapter 8 of the (11) . CEL A Cancer Effect Level (CEL) is the lowest exposure level associated with the onset of carcinogenesis in experimental or epidemiological studies. CELs are always considered serious effects. The LSE tables and figures do not contain NOAELs for cancer, but the text may report doses which did not cause a measurable increase in cancer. (12) . Footnotes Explanations of abbreviations or reference notes for data in the LSE tables are found in the footnotes. Footnote "c" indicates the NOAEL of 3 ppm in key number 18 was used to derive an MRL of 0.005 ppm. LEGEND See LSE Figure 2-1 LSE figures graphically illustrate the data presented in the corresponding LSE tables. Figures help the reader quickly compare health effects according to exposure levels for particular exposure duration. (13) . Exposure Duration The same exposure periods appear as in the LSE table. In this example, health effects observed within the intermediate and chronic exposure periods are illustrated. (14). Health Effect These are the categories of health effects for which reliable quantitative data exist. The same health effects appear in the LSE table. (15). Levels of Exposure Exposure levels for each health effect in the LSE tables are graphically displayed in the LSE figures. Exposure levels are reported on the log scale "y" axis. Inhalation exposure is reported in mg/m3 or ppm and oral exposure is reported in mg/kg/day. (16). NOAEL In this example, 18r NOAEL is the critical end point for which an intermediate inhalation exposure MRL is based. As you can see from the LSE figure key, the open-circle symbol indicates a NOAEL for the test species (rat) . The key number 18 corresponds to the entry in the LSE table. The dashed descending arrow indicates the extrapolation from the exposure level of 3 ppm (see entry 18 in the Table) to the MRL of 0.005 ppm (see footnote "b" in the LSE table). (17). CEL Key number 38r is one of three studies for which Cancer Effect Levels (CELs) were derived. The diamond symbol refers to a CEL for the test species (rat). The number 38 corresponds to the entry in the LSE table. 1 APPENDIX A (18) . Estimated Upper-Bound Human Cancer Risk Levels This is the range associated with the upper-bound for lifetime cancer risk of 1 in 10,000 to 1 in 10,000,000. These risk levels are derived from EPA's Human Health Assessment Group's upper-bound estimates of the slope of the cancer dose response curve at low dose levels (q^). (19) . Key to LSE Figure the figure. The Key explains the abbreviations and symbols used in VRD 0 0 0 2 0 U 2 5 1 A P P E N D IX A 0 TABLE 2-1. Levels of Significant Exposure to [Chenical xj - Inhalation Key to figure Species B-* INTERMEDIATE EXPOSURE 0- Systemic [T| S--* 0-- 18 Rat Exposure frequency/ duration System NOAEL (ppm) LOAEL (effect) Less serious (ppm) Serious (PPm) f 13 wk 5d/wk 6hr/d ? Resp f f 3b 10 (hyperplasia) Reference [| Mitschke et al 1981 CHRONIC EXPOSURE Cancer 38 Rat 18 mo 5d/wk 7hr/d 20 (CEL, multiple organs) Wong et al 39 Rat 89-104 wk 5d/wk 6hr/d 10 (CEL, lung tumors. NTP 1982 nasal- tunors) 40 Mouse 79-103 wk 5d/wk 6hr/d 10 (CEL, lung tumors. NTP 1982 hemangiosarcomas) 8 The number corresponds to entries in Figure 2-1. [12]--* b used to derive an intermediate inhalation Minimal Risk Level (MRL) of S x 10"3 ppm; dose adjusted for intermittent exposure and divided by an uncertainty factor of 100 (10 for extrapolation from animal to humans, 10 for hunan variability). CEL = cancer effect level; d * day(s); hr * hour(s); LOAEL * lowest-observed-adverse-effect levet; mo * month(s); MOAEL = no observed- adverse- effect level; Resp = respiratory; wk - week(s) ISZU0Z000 QHA f i l l --------------------------- INTERMEDIATE | 15-3M D a y | A* 6 APPENDIX A 8 VR0 000 2 03 7 2 51 Chapter 2 (Section 2.4) Relevance to Public Health A-7 APPENDIX A The Relevance to Public Health section provides a health effects summary based on evaluations of existing toxicological, epidemiological, and toxicokinetic information. This summary is designed to present interpretive, weight-of-evidence discussions for human health end points by addressing the following questions. 1. What effects are known to occur in humans? 2. What effects observed in animals are likely to be of concern to humans? 3. What exposure conditions are likely to be of concern to humans, especially around hazardous waste sites? The section discusses health effects by end point. Human data are presented first, then animal data. Both are organized by route of exposure (inhalation, oral, and dermal) and by duration (acute, intermediate, and chronic). In vitro data and data from parenteral routes (intramuscular, intravenous, subcutaneous, etc.) are also considered in this section. If data are located in the scientific literature, a table of genotoxicity information is included. The carcinogenic potential of the profiled substance is qualitatively evaluated, when appropriate, using existing toxicokinetic, genotoxic, and carcinogenic data. ATSDR does not currently assess cancer potency or perform cancer risk assessments. MRLs for noncancer end points if derived, and the end points from which they were derived are indicated and discussed in the appropriate section(s). Limitations to existing scientific literature that prevent a satisfactory evaluation of the relevance to public health are identified in the Identification of Data Needs section. Interpretation of Minimal Risk Levels Where sufficient toxicologic information was available, MRLs were derived. MRLs are specific for route (inhalation or oral) and duration (acute, intermediate, or chronic) of exposure. Ideally, MRLs can be derived from all six exposure scenarios (e.g., Inhalation - acute, -intermediate, -chronic; Oral - acute, - intermediate, - chronic). These MRLs are not meant to support regulatory action, but to aquaint health professionals with exposure levels at which adverse health effects are not expected to occur in humans. They should help physicians and public health officials determine the safety of a community living near a substance emission, given the concentration of a contaminant in air or the estimated daily dose received via food or water. MRLs are based largely on toxicological studies in animals and on reports of human occupational exposure. 0002037254 30 VRD 0002037255 A* 8 APPENDIX A MRL users should be familiar with the toxicological information on which the number is based. Section 2.4, "Relevance to Public Health,*' contains basic information known about the substance. Other sections such as 2.6, "Interactions with Other Chemicals" and 2.7, "Populations that are Unusually Susceptible" provide important supplemental information. MRL users should also understand the MRL derivation methodology. MRLs are derived using a modified version of the risk assessment methodology used by the Environmental Protection Agency (EPA) (Barnes and Dourson, 1988; EPA 1989a) to derive reference doses (RfDs) for lifetime exposure. To derive an MRL, ATSDR generally selects the end point which, in its best judgement, represents the most sensitive human health effect for a given exposure route and duration. ATSDR cannot make this judgement or derive an MRL unless information (quantitative or qualitative) is available for all potential effects (e.g., systemic, neurological, and developmental). In order to compare NOAELs and LOAELs for specific end points, all inhalation exposure levels are adjusted for 24hr exposures and all intermittent exposures for inhalation and oral routes of intermediate and chronic duration are adjusted for continous exposure (i.e., 7 days/week). If the information and reliable quantitative data on the chosen end point are available, ATSDR derives an MRL using the most sensitive species (when information from multiple species is available) with the highest NOAEL that does not exceed any adverse effect levels. The NOAEL is the most suitable end point for deriving an MRL. When a NOAEL is not available, a Less Serious LOAEL can be used to derive an MRL, and an uncertainty factor (UF) of 10 is employed. MRLs are not derived from Serious LOAELs. Additional uncertainty factors of 10 each are used for human variability to protect sensitive subpopulations (people who are most susceptible to the health effects caused by the substance) and for interspecies variability (extrapolation from animals to humans). In deriving an MRL, these individual uncertainty factors are multiplied together. The product is then divided into the adjusted inhalation concentration or oral dosage selected from the study. Uncertainty factors used in developing a substance-specific MRL are provided in the footnotes of the LSE Tables. ACGIH ADME ATS DR BCF BSC CDC CEL CERCLA CFR CLP cm CNS DHEW DHHS DOL ECG EEG EPA EKG FAO FEMA FIFRA *1 fpm ft FR g GC HPLC hr IDLH I ARC ILO in Kd kg Kc L LC LC Lo LC 50 LD Lo LD50 B-l APPENDIX B ACRONYMS, ABBREVIATIONS, AND SYMBOLS American Conference of Governmental Industrial Hygienists Absorption, Distribution, Metabolism, and Excretion Agency for Toxic Substances and Disease Registry bioconcentration factor Board of Scientific Counselors Centers for Disease Control Cancer Effect Level Comprehensive Environmental Response, Compensation, and Liability Act Code of Federal Regulations Contract Laboratory Program centimeter central nervous system Department of Health, Education, and Welfare Department of Health and Human Services Department of Labor electrocardiogram electroencephalogram Environmental Protection Agency see ECG Food and Agricultural Organization of the United Nations Federal Emergency Management Agency Federal Insecticide, Fungicide, and Rodenticide Act first generation feet per minute foot Federal Register gram gas chromatography high performance liquid chromatography hour Immediately Dangerous to Life and Health International Agency for Research on Cancer International Labor Organization inch adsorption ratio kilogram octanol-soil partition coefficient octanol-water partition coefficient liter liquid chromatography lethal concentration low lethal concentration 50 percent kill lethal dose low lethal dose 50 percent kill VRD 0002037256 VRD 0001031257 B-2 APPENDIX B LOAEL LSE m mg min raL mm mmol mppcf MRL MS NIEHS NIOSH NIOSHTIC nm ng NHANES nmol NOAEL NOES NOHS NPL NRC NTIS NTP OSHA PEL PS pmol PHS PMR ppb ppbC ppm ppt REL RfD RTECS sec SCE SIC SMR STEL STORET TLV TSCA TRI TWA lowest-observed-adverse-effect level Levels of Significant Exposure meter milligram minute milliliter millimeters millimole millions of particles per cubic foot Minimal Risk Level mass spectroscopy National Institute of Environmental Health Sciences National Institute for Occupational Safety and Health NIOSH's Computerized Information Retrieval System nanometer nanogram National Health and Nutrition Examination Survey nanomole no-observed-adverse-effect level National Occupational Exposure Survey National Occupational Hazard Survey National Priorities List National Research Council National Technical Information Service National Toxicology Program Occupational Safety and Health Administration permissible exposure limit picogram picomole Public Health Service proportional mortality ratio parts per billion parts per billion carbon parts per million parts per trillion recommended exposure limit Reference Dose Registry of Toxic Effects of Chemical Substances second sister chromatid exchange Standard Industrial Classification standard mortality ratio short-term exposure limit STORAGE and RETRIEVAL threshold limit value Toxic Substances Control Act Toxic Release Inventory time-weighted average IV V U.S. UF WHO < < X P 6 Y lim pg B-3 APPENDIX B United States uncertainty factor World Health Organization greater than greater than or equal to equal to less than less than or equal to percent alpha beta delta gamma micron microgram VRD 0002 0 3 72 58 VRD 0002037259 C-l APPENDIX C PEER REVIEW A peer review panel was assembled for 1,3-butadiene. The panel consisted of the following members: Dr. Arthur Gregory, Private Consultant, Techto Enterprises, Sterling, Virginia; Dr. V.M. Raraanujam, Associate Professor, Department of Preventive Medicine, University of Texas, Galveston, Texas; and Dr. Rogene Henderson, Biochemist, Lovelace Inhalation Toxicology Research Institute, Albuquerque, New Mexico. These experts collectively have knowledge of 1,3-butadiene's physical and chemical properties, toxicokinetics, key health end points, mechanisms of action, human and animal exposure, and quantification of risk to humans. All reviewers were selected in conformity with the conditions for peer review specified in the Comprehensive Environmental Response, Compensation, and Liability Act of 1986, Section 104. Scientists from the Agency for Toxic Substances and Disease Registry (ATSDR) have reviewed the peer reviewers' comments and determined which comments will be included in the profile. A listing of the peer reviewers' comments not incorporated in the profile, with a brief explanation of the rationale for their exclusion, exists as part of the administrative record for this compound. A list of databases reviewed and a list of unpublished documents cited are also included in the administrative record. The citation of the peer review panel should not be understood to imply its approval of the profile's final content. The responsibility for the content of this profile lies with the ATSDR. "U.S.Government Printing Office: 1992-- 636-291 VRD 0002037260 THE MRLtlUlNn IS A I.ISI CJF SUFFLICRS Of I.J I'lHAimHE.CRUDE HHADIfFI .UR UHllfi IMM'llflS. hT-F-f.OOUCIS.CCr. CUNIAININU I.J FUIADIIM ANO/IJR MS DIMER VJNTlCrLLbllLXf.FC III IIXACM chemical fACiutr ai i-mi neches from mi-iru* TEXACO CHEMICALIir80-lf8*T GULF(CHEVRON F. A. I TEXACO L.O.U. PACP CEDAR PATOU1KTERMAIU PAST WTANDOriC INfOK FARPJPE (TEXAS Cl IT, CALVENT CT> SYMtfc- ftECYCLE UNION CARPIDE IfAfT.SCAMIFT) >mn-warmer ___ COPOLYMER' fR RECYCLE IFSr FursvirsTfr LOUISVILLE RECYCLE POLYSAR CHATTAN CSSELON 'Auhii CHER I CAL _ CHEROT KtSUURCES NM1EIIPC VISTA CHEMICAL TEXAS EASTMAN ARCO -SUM HA0UAM1IC PHILLIPS.fiNCEFCT CHEVRON /* A UNION TEXAS CE1SMAR ASRC CNEM MKT ASSO. PETROMOHf rONCt TEXAS NORCHCM HEDITEA EL FASO CHEMICAL POLTSAR PCTROTEX ^-CHCMPIEX HlMHMMS mjiaota* FAIN 0Wtf/fM*XEAft oaiustUnt -- OLtnri* rt.tMM.kUR * CITIES SERVlOC *NMII*RN f-EIRO. CHEW. tollICNIAL OIL UNION IEXAS MULL.AM.SVN.L'VIUE PF 0-SYIP-QL-GULF11?4?-1 ?B0 > FMILL.COFDCO CEjAR PATOU !&X0h CALVERT CT TAFT 'N.FC/FHILIIF-S ctTrtx/r-Hia-aiNioN T.QfTRlLtiiT to. _ iiNimiL LOUISVILLE RECYCLE COHIUCNTAL OJL GULF(CHEV) CITIES SERVICE UNION TEXAS DO* EL FA50/1ND. SOL. IN'** rONIHCNIAL tffryisisNi GULF TCO-CHEM FETRD-TEX SHCLL-MHtrO/Tt TROTEX TEXAS OLEFIN ASIR AN* RHELTDN RECTCLt MONSAN(0_ SlNCLAIR-XOPFEKS EFUAr ' E.JJJUfOBF ''AtXJUJK-lt* SIHCINAINSIIIUTE RECYCLE IEXAS US(ITA^-lfUOt PEEFERSPN CHCrtlCAL F'E IftOSAR DOM ItlfcO-TET TEXAS-US IEXAS OLEFIN UNION CARPIDEI TAfl .SEATHiilFT I POfcG-VAKTCR TEXACO REF GEISHA* MOAII CHEMICAL CUMT.OIL/EXXON AMOCO ARCO tOHNUr A/C CHI Ml LEX AMENI CAM STN MARPON EL FASO PRODUCTS PHILLIPS AFCHOR-TEX PURE OIL TC T o o o o < X OJ 'O < 15 :d & > g: 10 2 2 o 2 o v/J . CO =J . ^ oe> O -J 2 ZZ UJ "* a: Q111 CO O CO => > Q O cc CL .1 ~ CO h---4 CO zc X UJ s. I9 1 L U 1 0 B * flSA FILE General Supplier Project Product Customer Other Q Existing SKNew File Name.' Environmental Health Perspectives tbl 100. pp 227-236. 1993 A L 9 lU 8 ld 8 d (m Carcinogenicity of 1,3-Butadiene by Ronald L. Melnick,' Cynthia C. Shackelford,' and James Huff1 13-Butadiene, a high-production volume chemical used lugely in the manufacture of synthetic rubber, is a multiple organ carcinogen in rab and mice. In inhalation studies conducted in mice by the National Toxicology Program, high rates of early lethal lymphomas occurring at exposure levels of 625 ppm or higher reduced the development and expression of later developing tumors at other sites. Use of survival-adjured tumor rates to account for competing risk hcton provided a clearer indication of the dose responses for 13-butadiene-induced neoplasms. An increase in lung tumors in female mice was observed at exposure concentrations as bw as &25 ppm, the lowest concentration ever used in a long-term carcinogenici ty study of this gas. Human exposures to 13-butadiene by workers employed at facilities that produce this chemical and at facilities that produce styrene-butadiene rubber haw been measured at levels higher than those that cause cancer in animals. Furthermore, epidemiology studtes have consistently revealed associations between occupational exposure to 13-butadiene and mens mortality due to lymphatic and hematopoietic cancers. In response to the carcinogenicity find ing for 13-butadiene in animate and in humans, the Occupational Safety and Health Administration has proposed lowering the occupational exposure standard for this chemical from 1000 ppm to 2 ppm. Future work is needed to understand the mechanisms of tumor induction by I3*butadiene; however, the pursuit of this research should not delay the reduction of human exposure to Ibb chemical. Introduction 1.3-Butadiene (CH2=CH=CH=CH2; CAS no. 106-99-0), a colorless, noncorrosive, flammable gas (boiling point: -4.4C). is produced mainly as a co-product in the steam cracking of petroleum fractions for the manufacture of ethylene (1). 1,3Butadiene is a reactive chemical that can dimerize to 4-vinylcyclohexene or, upon exposure to air, form explosive peroxides (/). The major uses of 1,3-butadiene are in the manufacture of synthetic rubber (such as styrene-butadiene rubber or polybuta diene rubber) and of thermoplastic resins. Butadiene elastomers are used in the manufacture of rubber tires, footwear, sponges, hoses, pipes, luggage, packaging, and a variety ofother molded products. 1.3-Butadiene is also used as an intermediate in the production ofother industrial chemicals. The annual production volume of 1.3-butadiene is approximately 12 billion pounds worldwide and 3 billion pounds in the United States (2,3). Based on its high volatility and low water solubility, en vironmentally released 1,3-butadiene partitions almost entirely into the atmosphere. According to a 1984 survey by the US. En vironmental Protection Agency, atmospheric emissions of 1.3-butadiene from facilities that produce or process this chemical totaled approximately 10 million pounds per year, with 70% of these emissions being attributed to equipment leaks and 30% to process venting (4). 1,3-Butadiene has also been iden tified in automobile exhaust, cigarette smoke, and gasoline 1 National Institute of Eiwironmental Health Sciences. P.O. Box 12233. Research Triangle Park. NC 27709. Address reprint rcquesBtoR. L. Melnick. National Institute of Environmental Health Sciences. P.O. Box 12233. Research Triangle ftrk, NC 27709. formulations, and small amounts are released by the burning of plastics or rubber (5). Low levels of 1,3-butadiene (0.5-10 ppb) have been detected in ambient air in urban locations in the United States; however, in community air at the perimeter of the in dustrial complex in fort Neches, Texas, where 1,3-butadiene and styrene-butadiene rubber are produced, levels as high as 2 ppm have been detected (6). Approximately 52,00 workers are potentially exposed to 1,3-butadiene in the United States, as estimated from data com piled from the National Occupational Exposure Survey (7). In recent industrial hygiene surveys at four monomer and Five polymer manufacturing plants, occupational exposures to 1.3butadiene were generally found to be less than 10 ppm; however, several maximum S-hr time-weighted average exposures and short-term exposures (15-120 min) were between 10 and 150 ppm, and in one case as high as 374 ppm, in operations involv ing decontamination and maintenance of process equipment, sampling and analyzing quality control samples, and loading or unloading tank trucks or rail cars (8). It is likely that exposures, especially short-term exposures, during the intensive wartime start-up of the synthetic rubber industry were greater than those in following years because of the rapid growth of the synthetic rubber industry during World War II and because during the 1940s, 1,3-butadiene was not considered to be hazardous to human health. In addition a high temperature, batch process was used in the early manufacture of styrene-b Jtadiene rubber. 1,3-Butadiene has long been considered to have a low and non- cumulative toxicity in animals and humai s. Early toxicology studies on 1,3-butadiene indicated that this < hemical only caused irritation to mucous membranes, skin, an< eyes, or narcosis at high concentrations (9). Human volume* rs exposed to 2000, VRD 0002037263 ::a MELS1CK ETaL k 4000. or 8000 ppm 1,3-butadiene for 6-8 hr experienced minor irritation to the eyes and difficulty in visual focusing, The studies by Carpenter et al. (9) in the 1940s formed the basis for the 8-hr time-weighted average workroom exposure concentration stan dard of 1000ppm subsequently promulgated by the U.S. Occupa tional Safety and Health ^ministration (OSHA): Results of re cent carcinogenicity studies of 1.3-butadiene in rats and mice (10-13) prompted the American Conference ofGovernmental In dustrial Hygienists to lower their recommended threshold limit value (TLV) for 1.3-butadiene in the work environment from 1000 ppm to 10 ppm (14). Meanwhile, OSHA has proposed lowering the occupational exposure standard for 1.3-butadiene to a permissible exposure limit (PEL) of 2 ppm with a 15-min short-term exposure limit (STEL) of 10 ppm (15). Hearings have been held, and a final decision on the proposed change is ex pected this year. Proceedings of an international symposium on the Toxicology, Carcinogenesis, and Human Health Aspects of 1,3-Butadiene were published in 1990 in Environmental Health Perspectives (16). This paper examines the carcinogenicity data of 1.3-butadiene in laboratory animats, with special emphasis on the influence of competing factors on tumor dose-response relationships, assesses the impact of recent mechanistic data on our understand ing of species sensitivity to 1,3-butadiene-induced carcinogen icity, and compares results of exposure to 1,3-butadiene in humans to results obtained in animals. Dose-Response for 1,3-ButadieneInduced Carcinogenicity in Mice and Rats In the absence of reliable epidemiological data, long-term studies in laboratory animals are the most reliable means of iden tifying potential health hazards, especially cancer, in humans. The carcinogenicity of inhaled 1,3-butadiene was studied in B6C3F, mice by the National Toxicology Program (NTP) (10.11) and in Sprague-Dawley rats by the International Institute of Syn thetic Rubber Producers (TISRP)(/2.13) to determine if there is a potential health hazard to humans. The NTP usually conducts experiments in Fischer 344 rats and B6C3Ft mice, and the dura tion of exposure is generally 2 years. Because the IISRP study was in progress at the time ofchemical selection, the NTP study was performed only in mice Inhalation Exposure of Mice to 625 or 1250 ppm 1,3-Butadiene Two long-term inhalation exposure studies of 1.3-butadiene in B6C3F, mice have been completed by the NTP. In the first study (10.11). groups of 50 male and 50 female mice were exposed 6 hr/day. 5 days/week to air containing 0 (chamber control). 625. or 1250 ppm 1,3-butadiene. These concentrations bracketed the OSHA standard of 1000 ppm. This study, designed to last for 103 weeks, was terminated after 60-61 weeks for humane reasons because of reduced survival at both exposure concentrations due to malignant neoplasms involving multiple organs in both sexes. Malignant lymphomas, which appeared to originate in the thymus and were observed as early as week 20, were considered to be the major cause ofearly deaths. Incidences of malignant lymphomas, hemangiosarcomas of the heart, and lung neoplasms were increased in both exposure groups of male and female mice compared with controls. Irons and co-workers confirmer by cytofluorofnetric analysis of cell surface markers that the t) pe of lymphoma caused by 1.3-buta diene in B6C3F, mice is a f-cell lymphoma (17,18). The high in cidences of hemangiosarc :>mas of the heart was a particularly unusual finding because th :se endothelial cell neoplasms are un common in B6C3F, mice, occurring only in one untreated male and one female mouse in the history ofthe NTP studies, and they have rarely been induced in long-term studies. Early induction and increased incidences of forestomach tumors were also observed in both sexes of mice, and increased incidences of tumors of the mammary gland, ovary, and liver were observed in females. These results demonstrate that 1,3-butadiene is a potent multi ple organ carcinogen in mice. However, dose-response relation ships were not always clear; for example, the incidences of hemangiosarcomas of the heart in male mice were 0/50 for con trols, 16/49 at 625 ppm, and 7/49 at 1250 ppm. Inhalation Exposure of Mice to 0-625 ppm 1,3-Butadiene A second long-term inhalation study of 1,3-butadiene in B6C3F, mice, over an expanded range of exposure concentra tions, was performed to better characterize dose-response rela tionships for neoplastic lesions induced by this chemical (19,20). Male and female mice were exposed to 0. 6.25.20.62.5, 200, or 625 ppm of 1,3-butadiene, 6 hr/day. 5 days/week for up to 2 years. The top exposure level was included to coincide with the low ex posure level in the first study. Survival was reduced for males and females exposed to 20 ppm or higher concentrations (Fig. 1). largely due to the development ofcompound-related fetal tumors. Again, thymic lymphoma, oc curring as early as week 23, was the major cause of death for male and female mice exposed to 625 ppm. The incidence of lymphoma was also increased in females exposed to 200 ppm. Tne incidences of hemangiosarcomas of the heart were in creased in male mice exposed to 62.5.200, and 625 ppm, and in female mice exposed to 200 and 625 ppm. In addition, one animal from the 20-ppm exposure group of males and one from the 62.5 ppm group of females were observed with this uncom mon endothelial cell tumor; these rare sarcomas are also most likely due to exposure to 1,3-butadiene. Interestingly, the incidence ofhemangiosarcomas of the heart was greater in male mice exposed to 200 ppm than in those ex posed to 625 ppm. This unusual dose-response was attributed to the early and extensive induction of lymphomas at 625 ppm that resulted in a significantly reduced number of mice at risk for the later-developing hemangiosarcomas. The effect of "competing risks" of early occurring lethal thymic lymphomas on the development of hemangiosarcomas of the heart is evident from the plots of the cumulative incidences of these neoplastic lesions against the number of weeks on study for male mice exposed to 200 or 625 ppm of 1,3-butadiene (Fig. 2). In the 625-ppm ex posure group, the incidence ofearly lymphoma was high (70%), and the incidence of hemangiosarcoma of the heart was low (5%), but in the 200-ppm exposure group, the incidence of early lymphoma was low (4%), and the incidence of hemangiosar coma of the heart (42%) was much higher than that in the 625-ppm exposure group. CARCINOGENICITY of 1.3 BUTADIENE * VRD 0002037264 PROBABILITY OF SURVIVAL A PROBABILITY OF SURVIVAL B Ficlre I. Kaptan-Meier survival curves for E6C3F, mice exposed to l.3-butadiene for 2 years. M) Male mice; (0) female mice. VRD 0002037265 130 MhLSb AL7AL A Weeks on Study Figure 2. Cumulative death-with-tumor rates for lymphomas or hemangiosarcomas of the heart versus weeks on study in male B6C3F, mice exposed to 200 or 625 ppm L.3-butadiene. Figure 3. Cumulative death-with-tumor rales for lymphomas or alveolar-bronchiolar neoplasms versus weeks on study in female B6C3F| mice exposed to 200 or 625 ppm 1.3-butadiene. The incidences of lung neoplasms in female mice were in..reased in all exposure groups. Thus, even at 6.25 ppm, l.3-butadiene is carcinogenic to B6C3F, mice. Because there were no exposure levels at which a carcinogenic response was not induced, it is likely that exposure concentrations below 6.25 ppm would also cause cancers in laboratory animals. Extrapolation ofthe dose-response curves to 2 ppm, the proposed OSHA stan dard for 1,3-butadiene, results in an estimated 2-fold increase in lung tumors in female mice. The reduced incidence of lung neoplasms at 625 ppm compared with the incidence at 200 ppm CARCINOGENICITY OF IJ BUTADIENE 231 * VRD 0802037266 Table 1. Sites of neoplasia and lowest significant effect level in male and female B6C3F, m...nk.c in the 2-year inhalation study of 1^-butadiene.* Site Lymphoma Heart Lung Forcbtorruch Liver Harderian gland Preputial gland Ovary Mammary gland Brain Kidney Small intestine Zymbal gland Skin Male mice 200 ppm + .62.5 ppm +'. 62-5 ppm + . 200 ppm +. 200 ppm +. 62.5 ppm +. 200 ppm NA +ru +OJi - Female mice -f. 20 ppm + . 200 ppm 6.25 ppm + . 625.ppm + .62.5 ppm + . 62.5 ppm NA + .62.5 ppm + .62.5 ppm - -- + 4- 'I +1 Increase relative to controls: (1 marginal increase relative to controls; I -) no difference from controls; NA. not applicable; U. uncommon tumor with nonsignificant increased incidence. was attributed to the high rate of early deaths due to competing risks of lymphoma in female mice exposed to 625 ppm (Fig. 3). For alveolar-bronchiolar neoplasms, the time-to- tumor detec tion was slightly shorter with exposure to 62S ppm than with ex posure to 200 ppm; however, because all the female mice ex posed to this concentration of 1,3-butadiene died by week 65, the final incidence of this later-developing and rarely lethal (lung) tumor was less than that for female mice exposed to 200 ppm. Neoplastic lesions ofthe forestomaeh, mammary gland, ovary, and liver, the other organ sites identified in the first study, were again increased in mice exposed to 1,3-butadiene. In addition, the Harderian gland, preputial gland, brain, and kidney were identified as sites of 1,3-butadiene-induced neoplasia (Table I). In unexposed chamber-control female mice, only benign neoplastic lesions were observed in the lung, Harderian gland, forestomach, and ovary: however, in female mice exposed to 1,3-butadiene, malignant neoplasms were observed in each of these organs (19,20). In particular, high incidences of alveolarbronchiotar carcinomas were observed in exposed female mice. Of the lung tumors observed in female mice exposed to 6.25 ppm 1,3-butadiene, 33% werealveolar-bronchiolarcarcinomas. The greater tendency toward malignancy in mice exposed to 1,3butadiene further demonstrates the strong carcinogenic poten cy of this chemical. Survival-adjusted Tumor Rates The impact of early mortality on the expression of late developing tumors was largely accounted for by adjusting for dif ferences in survival patterns. Survival-adjusted tumor rates for selected neoplasms are shown in Table 2 for male mice and in Table 3 for female mice, for the tumor incidences in these tables, numerators represent the number ofanimals bearing the specific neoplastic lesion, and denominators represent the adjusted number of animals at risk. The latter values were determined by combining the partial life experience for each of the animals in a particular exposure group. This combination was achieved by calculating the proportion of lifetime tumor risk observed for each animal. Animals that survived to the end ofthe study and animals that had the particular tumor in question (early death animals or animals that lived until the end of the study) were given a weight of one unit. The weight for an animal that died TkMc 2. Survival-adjusted rats of selected neoplasms Hi male B6C3F, mice la the 2-year Inhalation study of 1,3-butadiene.* Site: neoplasm Exposure concentration, ppm 0 6.25 20 62 5 200 625 Lymphoma 4/44.3 2/46.0 4/400 6/39.3 2/27.1 51/52.5 (9.0) (4.3) (10.0) (15.3) (7.4) (97.2)* Heart; hemangio sarcoma 0/43.2 045.0 (0.0) (0.0) 1/38.8 5/37.3 20/31 3 4/7.6 (2.6) (13.4)* 163.8)* (52.6)- Lung:alveolar-bron- 21/44.3 23/47.0 19/42.4 31/41.9 35/399 3-67 chiolar neoplasm (47 4) (48.9) (44 8) (74.0)* (877)* (448) `Incidence is given as the number of animals bearing a neoplastic lesion at a specific anatomic site divided by the adjusted number of animals at risk deter mined by the poly-3 survival-adjusted quanta! response method of ftriier and Bailer (2/). Survival-adjusted tumor rates are given in parentheses, as percentages 'Increased compared with chamber control (0 ppm). p< 005. Tkbie 1 Survival-adjusted rates atselected neoplasms In female B6C3F, mice in the 2-vear inhalation study of (3-butadiene.* Exposure concentration, ppm Site; neoplasm 0 625 20 62.5 200 625 Lymphoma 6/46.0 12/44.3 11/40.1 (DO) (27.1) (27.4) II 9/22.6 32/375 (39.8)* (85.3)* Heart; hemangiosarcoma 0/45.4 (0O) 0/44.1 (0.0) 0/38.8 (0.0) 1/32.7 21/29.3 23/276 (3.1) (71.61* (83.2)* Lung:alveolar-bron- 4/45.5 chiolar neoplasm (8.8) Ovary:gtanulosa cell 1/44.4 neoplasm (2.3) 15/45.5 19/41.0 24/39.4 25/30.8 22/268 (33.0)' (46.3)* (60.9)* (81.3)* (82.2)* 0/44.1 (0.0) 1/38.2 9/34.2 8/19.5 6/12.9 (2.6) (26.3)* (41.1)* (465)* Mammary gland; adenocarcinoma or adenoacanthoma 0/45.4 (0.0) 2/44.1 (4.5) 4/39.2 12/36.8 15/26.6 16/240 00.21* (32.6)' (56.4)- (66.8)* `Incidence is given as the number of animals bearing a neoplastic lesion at a specific anatomic site divided by the adjusted number of animals at risk deter mined by the poly-3 survival-adjusted quanta! response method of Ponier and Bailer (2/>. Survival-adjusted turror rales are given in parentheses, as percentages. 'Increased compared with chamber control (0 ppm), p <0.05. before study termination but was free ofthe tumor being analyzed was estimated by calculating the fractional survival time on study for that animal raised to the third power. For example, an animal that did not have a hemangiosarcoma of the heart and died due to lymphoma after about 1/3 of the study (approximately 35 weeks) had (1/3)3 or about 0.04 risk for the development of the heart tumor, as compared to an animal living for the full study: however, ifthat animal had survived for 2/3 of die study (approx imately 70 weeks), it would have contributed a weight of (2/3)} or about 0.30. This survival-adjusted "poly-3 quantal response'* method has been described by fortier and Bailer (21). The use of the third pewer was selected because cumulative tumor rates have been found to occur generally as a third- to fourth-order function ofage in animals. Simulation experiments have shown that this method is valid (correct false-positive error rate) even when the actual values for the power are as low as 1 or as high as 5(22). The survival-adjusted tumor rates provide a clearer indication of the dose-responses for neoplasms caused by 1,3-butadiene. The apparent downturn in response for hemangiosarcomas of the heart and lung neoplasms in male mice exposed to 625 ppm l,3-butadiene was substantially, but not totally, reversed by ad justing for reduced survival. Because ofthe large number ofearly deaths due to lymphoma at this exposure level, the adjusted AttiSiLh t / AL number of animals at risk for developing heart or lung tumors was less than 10. At lower exposure concentrations, where ear ly death due to lymphon-a was not a major competing factor, there was a much larger 2 djusted number of animals at risk for these later developing tui iors. Thus, not unexpectedly, the 200 ppm exposure group ha< the largest number of animals with heart and lung tumors. In female mice, the inc idence of lymphoma at 625 ppm was less than that in male mi :e. Consequently, tumor responses at other sites were not as dr* stically affected in females as in males at this exposure level. Except for the ovary, the adjusted number of animals at risk for the later-developing'tumors was approx imately 25. As the concentration of 1,3-butadiene was reduced from 625 ppm to 6.25 ppm, survival was increased and the ad justed number of animals at risk increased steadily for each of these sites. The high adjusted number of male or female mice at risk for lymphoma at 625 ppm reflects the high incidence of this life-shortening neoplastic lesion. For tumors showing exposure related effects, the shapes ofthe dose-response curves were estimated by Fitting a modified Weibull model (23) to the poly-3 survival-adjusted tumor rales (20). For approximately half of the tumors evaluated, the dose response was consistent with a linear model (forestomach neoplasms in males and females, hemangiosarcomas of the heart and preputial gland tumors in males, and lymphoma, liver, and ovarian neoplasms in females). In most instances in which a departure fmm linearity was evident, the shape parameter in dicated a dose-response curve that was supralinear (concave downward) in the low dose region (lung and Harderian gland neoplasms in males and females, liver neoplasms in males, and mammary gland tumors in females). Only for lymphoma in male mice and hemangiosarcoma ofthe heart in female mice was there evidence of a sublinear (concave upward) dose-response curve. The inhalation studies conducted at 6.25-625 ppm 1,3-butadiene provide a better characterization of the concentrationdependent responses for 1,3-butadiene-induced cancers than did the studies at 625 and 1250 ppm. The observation of carcinogen icity at all exposure levels studied demonstrates that carcinogenic responses occur over a 200-fold concentration range in mice. Stop-Exposure Studies Stop-exposure studies were designed to assess the relationship between exposure level and duration ofexposure on the outcome of 1.3-butadiene-induced carcinogenicity and to consider the ef fect of variable worker exposure patterns. These studies were conducted by exposing groups of 50 male mice to one of the following regimens: a) 200 ppm for 40 weeks: b) 625 ppm for 13 weeks; c) 312 ppm for 52 weeks; or d) 625 ppm for 26 weeks (19,20). After the particular exposures were terminated, these groups of animals were placed in control chambers for the re mainder of the 104 week studies. The total exposure to 1,3-butadiene (concentration limes duration of exposure) was approx imately equivalent for the First two groups (8000 ppm-weeks for groups a and b) and provided about half the total exposure given to the latter two groups (16,000 ppm-weeks for groups c and d). The tumor incidence profiles in the stop-exposure groups showed that lymphomas, hemangiosarcomas of the heart, and tumors of the lung, forestomach, Harderian gland, and preputial gland were increased even after only 13 weeks ofexposure to 625 IhMe 4. Survival-adjusted rates for lymphoma and hemangiosamxna of the heart in the slop-exposure (SE) groups of male B6C3F, mice exposed to 1.3-butadiene.* Exposure concentration, pptn Site: neoplasm 0 (control) 200 ppm SE 40 weeks (8,000)b 625 ppm SE 13 weeks (8.125) 312 ppm SE 52 weeks (16.224) 625 ppm SE 26 weeks (16.250) Lymphoma 9.0 24.1 56.1- 35.0- 87.2- Heart: hemangiosarcoma 0.0 47.1- 30.9- 85.2* 74.5' `Survival-adjusted tumor rates, determined by the poly-3 survival-adjusted quanta! response method of ft>rtier and Bailer (2D, are given as percentages. ^Total exposure expressed as ppm-weeks. `Increased compand with chamber control (0 ppm). p < 0.05. ppm of 1,3-butadiene (19,20). It is likely that even shorter ex posure durations would also produce a positive carcinogenic response. Furthermore, at comparable total exposures, the in cidence oflymphoma was greater with exposure to a higher con centration of 1,3-butadiene for a short time compared with ex posure to a lower concentration for an extended duration. This is evident by comparing the adjusted incidence of lymphoma in the 625 ppm 13-week stop-exposure group (56%) with that in the 200-ppm 40-week stop-exposure group (24 %), or by comparing the incidence in the 625 ppm 26-week stop-exposure group (87%) with that in the 312 ppm 52-week stop-exposure group (35%) (Table 4). Thus, for the development of thymic lym phomas, the concentration of 1,3-butadiene is a greater con tributing factor than is the duration of exposure. For other tumor types, e.g., hemangiosarcomas of the heart, the rates appeared to be dependent on the multiple ofexposure concentration times the duration of exposure. Carcinogenicity of 1,3-Butadiene in Rats In the carcinogenicity study conducted by the DSRP in rats, groups of 100 animals of each sex were exposed to 0, 1000, or 8000 ppm 1,3-butadiene for 6 hr/day, 5 days/week for 2 years (12,13). Under the conditions of this study, 1,3-butadiene was carcinogenic at multiple organ sites, as evidenced by increased incidences and/or dose-response trends for several organspecific cancers: pancreatic exocrine neoplasms and Leydig cell rumors ofthe testis in males and uterine stromal sarcomas, Zytri bal gland carcinomas, mammary gland fibroadenomas and car cinomas, and thyroid follicular cell neoplasms in females. The increase in mammary gland fibroadenomas was further related to exposure to 1,3-butadiene because the average number of mammary gland fibroadenomas per rat bearing a mammary gland tumor was increased in both exposure groups compared to controls. The occurrence of uncommon glial cell tumors of the brain in exposed male rats may also have been related to exposure to 1,3-butadiene. The incidences ofbrain, uterine, and mammary gland tumors were not much higher in the 8000-ppm exposure group compared to the KXX) ppm exposure group. The nearly level dose response for these tumors was probably due to satura tion of 1,3-butadiene metabolism in Sprague-Dawley rats, which occurs at exposure concentrations between 1000 and 2000 ppm. Unlike the response in mice, there were no increases in the incidences of lymphoma/leukemia, or neoplasms of the lung, heart, forestomach, ovary, liver, Harderian gland, or preputial ,VRD 0002037267 A CARCINOGENICITY OF J.3 BUTADIENE 233 A VRD 000203T268 gland in Sprague-Dawley rats of either sex exposed to 1000 or 8000 ppm 1,3-butadiene. CM,-CmCh.ch? NAOPH Oj n<rosoms Mechanistic Studies of 1,3-Butadiene Carcinogenicity and Relevance to Human Risk Influence of Murine Retrovirus Recent experimental research has been aimed at understanding the mechanisms of tumor induction by 1.3-butadiene. Irons and co-workers compared the induction of thymic lymphomas and the expression of murine leukemia retrovirus in B6C3F, mice and in NIH Swiss mice exposed to 1,3-butadiene for 52 weeks (17.18,24). The Swiss strain of mouse was used because it does not express the ecotropic murine leukemia viruses expressed in B6C3F[ mice, and it has a background rate of nearly zero for thymic lymphoma. The finding that 1 year of exposure to 1250 ppm 1.3-butadiene caused a 14% incidence of thymic lympho mas in NIH Swiss mice shows clearly that 1,3-butadiene induces this neoplasm independently of these activated retroviruses. DNA Adducts Reaction products of guanine with l,2-epoxy-3-butene or diepoxybutane were detected in liver DNA of B6C3F, mice, but not in liver DNA of Wistar rats, exposed to 500 ppm (MCJ1,3butadiene {25). Future work is needed on DNA adduct forma tion in the major target sites of 1,3-butadiene carcinogenicity in B6C3F, mice and in Sprague-Dawley rats at the exposure con centrations used in the 2-year studies. Furthermore, the nature of the covalently bound [`X)l,3-butadiene-derived radioactivity to rat liver DNA (26) is yet to be determined. Metabolism and Pharmacokinetics Studies on the metabolism and pharmacokinetics of 1,3-buta diene in rats and mice have been undertaken to investigate and ex plain species differences in organ site specificity and potencies of 1,3-butadiene-induced carcinogenicity. Biotransformation of 1.3- butadiene is probably an important factor in the car cinogenicity of this compound because the in vitro mutagenici ty of 1.3-butadiene requires metabolic activation (27), and epox ide intermediates of 1,3-butadiene metabolism are mutagenic in Salmonella typhimurium (28,29) and are carcinogenic in rats and mice (30,31). l,2-Epoxy-3-butene, the first intermediate of 1,3-butadiene metabolism (32), is formed by an inducible rat liver microsomal cytochrome P-450 monooxygenase (33) (Fig. 4). l.2-Epoxy-3butene has been detected in expired air of Sprague-Dawley rats (33.34) and of B6C3F, mice (35) exposed to 1,3-butadiene, indi cating that this epoxide intermediate is systemically available in exposed animals. Further metabolic transformation of l,2-epoxy-3-bulene involves conjugation with glutathione by glutathione-S-transferase, ox dationto l,2:3,4-diepoxybutane, or hydrolysis by epoxide hydrolase and further oxidation to 3.4- epoxy-l,2-butanediol (3{). Saturation of 1,3-butadien: metabolism in Sprague-Dawley rats and in B6C3F, mice was reported to occur at atmospheric concentrations between KX> and 2000 ppm (37). The rate of metabolism of 1,3-butadiene in mice is about two times higher Ch2.Cm-Cm-Ch2 11 O 2EooyJ-ouiene1' eoo>4 hyO'das* . NACH Oj irucrosOT'es CHj.CH-ChOh-CMjOh 3Btn*-t.2oi NAOPH Clj m<ra$oms CMjCh-CmOh-CHjOH \/ O 3.*Eoo*y-v2 -Dotanadiol o /\ Ch2 Ch-Ch-CHj \/ O 0<*DOiyOu'arv Figure 4 Metabolism of l,3-but*dine. than that in rats (37,38). This increase is probably due to the higher respiratory frequency ofmice (37). Titus, risk assessment models that account for breathing rate differences between species adjust for the major factor that distinguishes the increased metabolic rate for 1,3-butadiene in mice compared to rats. Steady-state concentrations of l,2-epoxy-3-butene are approx imately six times higher in mice than in rats exposed to the same atmospheric concentration of 1,3-butadiene; however, about half ofthis difference is attributed to the higher breathing rate ofmice compared to rats (39). Pharmacokinetic studies of 1,3-butadiene in rats and mice have not revealed species differences ofsufficient magnitude to account for the different carcinogenic responses seen in these two species (59). Evidently, other factors are involved in distinguishing site-specific differences in the carcin ogenicity of 1,3-butadiene between species, including humans. More work is needed to understand species differences in 1,3butadiene pharmacokinetics, metabolic differences and reactivity ofmetabolic intermediates with DNAat target sites, differences in detoxification or mechanisms of repair, and the impact these factors may have on 1,3-butadiene-induced carcinogenesis. Epidemiology Studies Associations between occupational exposure to 1,3-butadiene and increased risk of cancer have been evaluated in retrospective mortality studies of workers employed at facilities that produce 1,3-butadiene (40,41) and at facilities that produce styrenebutadiene rubber (42-44). Excess mortalities from lymphatic and hematopoietic cancers among subgroups of occupationally exposed workers in each of these studies provides strong evi dence for the carcinogenicity of 1,3-butadiene to humans. Rates ofmortality for lymphosarcoma and reticulum cell sarcoma were increased by as much as 5.6*fold among workers in a 1,3-butadiene manufacturing plant (40), while 5- to 6.6-foJd in creases in mortality from all lymphopoietic cancers and leukemia were reported among black workers in the production areas of styrene-butadiene-rubber plants (44). In a nested casecontrol study in which the cases of lymphopoietic cancers were compared to an internal population of workers who did not have cancer. Matanoski et al. (45) found that the excess leukemias in MELWCK ETAL. A VRD 0607037269 the styrene-butadiene rubber industry were associated with ex posure to i,3-butadiene and not to styrene. Because the epidemiology studies lacked quantitative ex posure data, some have considered duration of employment within broad work job classifications to be an Indication of human exposure (46,47). This relationship is probably not valid for the l.3-butadiene or styrene-butadiene rubber production in dustries because there have been large variabilities in exposures associated with specific tasks, especially during the rapid giwth of the synthetic rubber industry during World War II, and because process changes in the production of 1,3-butadiene and in the production of styrene-butadiene rubber probably affected workplace exposures over the past 50 years. Thus, not surpris ingly. increased mortality for lymphopoietic cancers was most striking among workers first hired in the 1.3-butadiene and styrene-butadiene-rubber plants during World War II (40-42). Relevant to this issue are the results of the stop-exposure studies in mice, where the exposure concentration of 1,3-butadiene was a greater contributing factor to the development ofthymic lym phomas than was the duration of exposure (19,20). Conclusions 1.3-Butadiene is a high-production-volume chemical used largely in the manufacture of synthetic rubber. The production and use of 1,3-butadiene increased dramatically during World War II with the development of the synthetic rubber industry. Before the 1980s, 1.3-butadiene was not considered to be par ticularly hazardous to human health; therefore, OSHA estab lished a permissible limit of 1000 ppm for occupational exposure to this chemical. Results of recent inhalation carcinogenicity studies have demonstrated clearly that 1,3-butadiene is a multiple-organ carcinogen in Sprague-Dawley rats and in B6C3F, mice. J^rticularly noteworthy in mice were the early oc currences and extensive development of lymphomas, the induc tion of uncommon hemangiosarcomas of the heart, and the development of malignant lung tumors at exposure concentra tions as low as 6.25 ppm. Because 6.25 ppm was the lowest con centration ever used in a long-term carcinogenicity study ofthis gas. it is likely that lower exposure levels would also cause cancers in laboratory animals. In addition, multiple organ site neoplasia was induced in mice after only 13 weeks of exposure. The conclusion that the marginally increased incidences of hepatocellular neoplasms in male and female mice were chemically related is strengthened by the detection of activated K-ras oncogenes with a specific codon 13 mutation in liver neoplasms obtained from mice exposed to 1.3-butadiene (45) in the carcinogenicity studies (19,20). Activated K-nar oncogenes have never been detected in liver tumors from untreated B6C3F, mice (49). Activated K-raj genes by codon 13 mutations were also found in lung neoplasms and in some of the lymphomas in duced by exposure to 1.3-butadiene. In addition, Wiseman and Barrett (50) showed that tumor-suppressor genes are inactivated during 1,3-butadiene carcinogenesis. The detection of activated K-raj oncogenes and inactivated tumor suppressor genes in rumors induced by 1.3-butadiene adds further relevance to the potential carcinogenicity of 1.3-butadiene in humans because K-ror is the most commonly detected oncogene in human cancers, and allele losses are common in human cancers. The important issue of competing risks has received little at tention in the evaluation of long-term chemical carcinogenesis experiments. The studies of [,3-butadiene in mice illustrate the nej to adjust tumor incidence data for survival differences among groups to provide reliable dose-response daa when com peting risk factors obscure the development and detection of later-developing neoplastic lesions. The poly-3 quanta! response method was used to adjust for the number of animals at risk and thereby provide survival-adjusted tumor rates. For most of the tumors evaluated, the dose responses were consistent with a linear curve or supralinear curve in the low dose region. For only two tumor responses was there evidence of a sublinear doseresponse curve. Two reactive epoxides. l,2-epoxy-3-buieneand diepoxybutane, have been identified as intermediates in the biotransformation of 1,3-butadiene in rats and mice. Metabolism is probably an im portant factor in the carcinogenicity ofl,3-buiadiene because in vitro mutagenicity of 1.3-butadiene requires metabolic activa tion, whereas these epoxide intermediates are direct-acting mutagens in bacteria and are carcinogens in rats and mice. The metabolism of 1.3-butadiene in rats and mice is linear up to concentrations ofat least 1000 ppm. Pharmacokinetic studies on 1,3-butadiene and on l,2-epoxy-3-butene have revealed certain quantitative differences in metabolic rates for these chemicals in Sprague-Dawley rats and B6C3F, mice; however, these dif ferences were not of sufficient magnitude to account for the reported different target site carcinogenic responses in these two species. Thus, additional factors mustbe involved indistinguish ing site specificity in the carcinogenicity of 1,3-butadiene between species. Epidemiology studies of workers employed in the production of 1,3-butadiene or of styrene-butadiene rubber have consistently revealed associations between occupational exposure to 1,3-butadiene and excess mortality due to lymphatic and hematopoietic cancers. The excess leukemias in the styrenebutadiene rubber industry were associated with exposure to 1,3-butadiene and not to styrene. The results from studies in humans correspond to the increases in lymphoma observed in mice exposed to 1,3-butadiene. Based on the evidence ofcarcinogenicity for 1,3-butadiene in humans and in experimental animals, the International Agency for Research on Cancer has concluded that 1.3-butadiene is pro bably carcinogenic to humans (5). In response to the findings that 1,3-butadiene is a potent carcinogen in animals and that human exposure to 1,3-butadiene is associated with excess mortalities due to lymphatic and hematopoietic cancers. OSHA has pro posed to lower the occupational standard for this chemical from 1000 ppm to 2 ppm (A5). The determination of this 500-fold decrease was based largely on data from the NTP carcinogenicity studies of 1.3-butadiene in mice. Future research on 1,3-butadiene is needed to elucidate mechanisms of 1,3-butadiene-induced carcinogenicity and to more fully assess human mortality outcomes with better quan titative estimates of past and present exposures. The pursuit of these research objectives should not delay the reduction of human exposure to this chemical. CARCINOGENICITY OF 1.3-BUTADIENE 235 REFERENCES I Kirshenbaum. I Buudiene. In: Kirk-Olhmer Encyclopedia of Chemical Technology. Vbl 4. 3rd ed John Wiley and Sons. New York. 1978, pp. 313-337. 2. .Morrow. N L. The industrial production and use of 1.3-butadiene Environ. Health ftrspect. 86 7-8 Il990i. 3 '"USJTC Synthetic Organic Chemicals United States Production and Sales 1989 Publication 2338. United States International Trade Commission. U S Government Priming Office. Washington. DC. 1990. 4 Mullins. J A Industrial emissions of 1,3-butadiene. Environ Health Perspecl 86 9-10(1990) 3. IARC IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Strong Acid Mists and other Industrial Exposures. Vbi. 54. Inter national Agency for Research on Cancer. Lyon'. France, in press 6 Durchin. J Sampling and analysis of the ambient air in the area of fcn Neches. Jefferson County. Texas. Final Report. Sampling and Analysis Divi sion. Monitoring Operations. Texas Air Control Board. Austin. TX. 1990. 7 NIOSH National Occupational Exposure Survey (1981-1983) National In stitute for Occupational Safety and Health. Cincinnati. OH. 1990. 8 Fajen.) M.. Roberts. D R . Ungers. L. J.. and Krishrun. E R Occupa tional exposure of workers to 1.3-butadicne Environ. Health Perspect 86: 11-18(1990). 9. Carpenter. C. P.. Shaffer. C. B.. Weil. C. S.. and Smyth. H. F Studies on the inhalation of 1.3-butadiene, with a comparison of its narcotic effect with benzol, toluol, and styrene, and a note on the elimination of styrene by the human J Ind. Hyg. Toxicol 26: 69-78 (1944). 10. NTP Toxicology and Carcinogenesis Studies of 1.3-Butadiene (CAS No. 106-99-0) inB6C3F, Mice (Inhalation Studies). National Toxicology Pro gram Technical Report No. 288. National Institutes of Health. Bethesda, MD. 1984. 11. Huff. J. E.. Melnick. R. L.. Solleveld. H. A.. Haseman. J. K.. ftwrv M.. and Miller. R. A Multiple organ carcinogenicity of 1.3-butadicne in B6C3F| mice after 60 weeks of inhalation exposure. Science 227:548-549 (1985). 12. IISRP The Toxicity and Carcinogenicity of Butadiene Gas Administered to Rats by inhalation for Approximately 24 Months. International Institute of Sy nthetic Rubber Producers Report No. 2653-522/2. Houston. TX. 1981. 13 Owen. P E.. Glaister. JR. Gaunt, i. F.. Pullinger, D H. Inhalation tox icity studies with 1.3-butadiene. 3. Two-year twicity/carcinogenicity studies m rats Am. Ind. Hyg. Assoc. J. 48: 407-413 (1987). 14. ACGIH. Documentation of the threshold Limit Values and Biological Ex posure indices. American Conference of Governmental Industrial Hy gienists. Cincinnati. OH. 1986. pp 68-70. 15 Occupational Safety and Health Administration. Occupational exposure to 1.3-butadiene: proposed rule and notice of hearing. Fed. Reg. 55: 32736-32826(1990). 16 Melnick. R. L.. Huff. J E. Bird. M. G.and Acquavella.J. F. Symposium overv iew . Toxicology, Carcinogenesis, and Human Health Aspects of 1.3Butadiene. Environ. Health Perspect. 86: 3-5 (1990). 17 Irons. R. D.. Cathro. H P.Stillman. W. S., Sleinhagen, W. H., and Shah, R. S. Susceptibility to 1.3-butadiene-induced leukemogenesis correlates with endogenous ecotropic retroviral background in the mouse. Toxicol. Appl. Pharmacol. K)t: 170-176(1989). 18. Irons. R. D. Studies on the mechanism of 1.3-butadiene-induced leukemo genesis: The potential role of endogenous murine leukemia virus. Environ. Health Perspect. 86: 49-55(1990). 19. Melnick. R. L.. Huff. J.. Chou. B. J.. and Miller. R. Carcinogenicity of 1.3-butadiene in C57BU6 x C3H F, mice at low exposureconcemrations. Cancer Res. 50: 6592-6599 (1990). 20. NTP. Toxicology and Carcinogenesis Studies of 1.3-Buladiene (CAS No. 106-99-0) inB6C3F| Mice (InhalationStudies). National Toxicology Pro gram Technical Report No 434, National Toxicology Program. Research Triangle Park. NC. in press. 21 Portier. C. X. and Bailer. A J Testing for increased carcinogenicity using a survival-adjusted quanta! response test. Fundam. Appi. Toxicol. 12:731-737 (1989). 22. Bailer. A. J . and Ponier. C. J. Effects of treatment-induced mortality and tumor-induced mortality on tests for carcinogenicity in small samples. Biometrics 44: 417-432(1988). 23. Fbrtier. C. J.. Hedges. J. C.and Hoel. D G. Age-specific models ofmortal ity and tumor onset for historical control animals in the National Toxicology Program's carcinogenicity experiments. Cancer Res. 46: 4J72-4378 (1986). 24. Irons. R D . Stillman. W. S . and Cloyd. M. W. Selective activation of endo genous ecotropic retrwiros in hematopoietic tissues of B6C3F, mice dunng the preleukemic phase of 1.3-butadiene exposure. Virology 161: 457-462 (1987) 25. Jelitio. B . Vbngala.R. R . and LaibR J. Species differences in DNA damage by butadiene: role of diepoxy butane Arch. Toxicol. 13: (Suppl.) 246-249 (1989). 26 Kreihng. R. Laib. R. J.. and Bolt. H M. Alkylation of nuclear proteins and DNA after exposure of ras and mice to (1.4-l4C]L3-butadiene Toxicol. Lett 30 131-136(1986) 27. de Mcester. C.. Poncelet. F.. Roberfroid. M . and Mercier. M The mutagenicity of butadiene towards Salmcnetla nphimurium Toxicol. Lett. 6 125-130(1980). 28. de Meester. C , foncelet. F. Roberfroid. M . and Mercier. M. Mutagenicity of butadiene and butadiene monoxide Biochem. Biophys. Res. Commun. 80: 298-305 0978). 29. Wade. M. I, Moyer. J. W'., and Mine. C. H Mutagenic action of a series of epoxides. Mum Res. 66 367-371 0979). 30 Van Duuren. BL. Nelson. N.. Orris. L.. Palmes. ED. and Schmitt. F. L. Carcinogenicity of epoxides, lactones, and peroxy compounds J. Natl. Cancer Inst. 31: 41-55 (1963). 31. Van Duuren. B. L.. Langseth, L-. Orris L.. Teebor. G.. Nelson. N.. and Kuschner. K. Carcinogenicity of epoxides. lactones, and peroxy compounds. IV Tumor response in epithelial and connective tissue in mice and rats. J. Natl. Cancer Inst. 37: 825-838 (1966). 32. Maivoisin. E., Lhoest. G.. Poncelet. F . Roberfroid. M .and Mercier. M. Identification and quantitation of 1.2-epoxybutene-3 as the primary metabolite of 1.3-butadiene. J. Chromatogr. 178: 419-425 (1979). 33. Bolt. H. M.. Schmiedel. G.. Filser. J. C.. Rolzhauser, H. P, L.eser. K . Wistuba. D .and Schurig. V. Biological activation of 1.3-butadiene to vinyl oxirane by rat liver microsomes and expiration of the reactive metabolite by exposed rats. Cancer Res. Clin. Oncol. 106: 112-116 (1983). 34. Filser. J. G., and Boll. H. M . Inhalation pharmacokinetics based on gas up take studies. VI. Comparative evaluation of ethylene oxide and butadiene monoxide as exhaled reactive metabolites of ethylene and 1.3-butadiene in rats. Arch. Toxicol. 55: 219-223 (1984). 35. Kreiling. R.. Laib. R. J.. Filser. J. G . and Bolt. H. M. Inhalation phar macokinetics of l.2-epoxybutene-3 reveal species differences between rats and mice sensitive to butadiene-induced carcinogenesis. Arch. Toxicol. 61: 7-11 (1987). 36. Maivoisin. E.. and Roberfroid. M. Hepatic microsomal metabolism of 1.3-butadiene. Xenobiotica 12: 137-144 (1982). 37. Kreiling. R, Laib, R. Filser. J. G.. and Bolt, H. M. Species differences in butadiene metabolism between mice and rats evaluated by inhalation phar macokinetics. Arch. Toxicol. 58: 235-238 (1986). 38. Bolt. H. M.. Filser. J. G.. and Stormer. F. Inhalation pharmacokinetics based on gas uptake studies. V. Comparative pharmacokinetics of ethylene and 1.3-butadiene in rats. Arch. Toxicol. 55: 2I3-2I8 (1984). 39. Melnick. R. L., and Huff, J. 1.3-Butadiene: toxicity and carcinogenicity in laboratory animals and in humans. Rev. Environ. Cornam. Toxicol. 124: 111-144 (1992). 40. Downs. T. D., Crane. M M . and Kim. K. W. Mortality among workers at a buudiene facility. Am. J. Ind. Med 12 : 311-329 (1987). 41. Divine. B. J. An update on mortality among workers at a 1.3-buudiene facil ity -- preliminary results. Environ. Health Perspect. 86: 119-128 (1990) 42. Meinhardt, T. J.. Lenten, R. A.. Crandall, M. S., and \bung. R. J. En vironmental epidemiologic investigation of the styrene-butadiene robber in dustry. Scand. J. Work Environ. Health 8: 250-259 (1982). 43. Matanoski, G. M . and Schwartz, L. Mortality of workers in styrenebuudieoe polymer production J Occup. Med. 29: 675-680 (1987) 44. Matanoski, G. M.. Santos-Burgoa. C . and Schwartz. L. Mortality ofa cohort of workers in the styrene-butadiene polymer manufacturing industry (1943-1982). Environ. Health Perspect 86: W7-U7 (1990). 45. Matanoski, G. M., Samos-Burgoa. C.. Zeger. S. L . and Schwart2. L Epidemiologic dau related to health effects of 1.3-butadiene. In: Assessment of Inhalation Hazards (U. D. Mohr. D. V. Bates. K. L. Dungworth, P. N. Lee. R. O McCellan. and F J. C Roe, Eds ), Springer-Vcrlag. New York. 1989, pp. 201-214 46 taquavella, J. F. Future directions in epidemiologic studies of 1,3-butadieneexposed workers. Environ. Health Perspect. 86: 129-134 (1990). 47. On. M. G. Assessment of 1,3-butadiene epidemiology studies. Environ. Health Perspect. 86: 135-141 (1990). A 8 L IL IB IB B B GM VRD MELNICK ETAL 18. Goodrow. T., Reynolds. S.. Maronpot, R.and Anderson. M. Activation of K-ras by codon 13 mutations in C57BL/6 x C3H F, mouse turnon induced by exposure to 1.3-butadiene. Cancer Res. 50: 4818-4823 (1990). 49. Reynolds. S. H.. Stowers. S. I.. Patterson. R. M.. Maronpot. R. R., Aaronson. S. A.. and Anderson. M. W. Activated oncogenes in B6C3F, mouse liver tumors: implications for risk assessment. Science 237: 1309-1316(1987). 50. Wiseman. R. W . and Barrett, J. C. Loss of heterozygosity on chromosome 4 m butadiene-induced lung tumors of B6C3F, mice. Am. Assoc. Cancer Res. 31:317 (1990). IS e 1-0 CSS uo