1,3-Butadiene (BD) exposure's link to leukemia is under regulatory scrutiny. The assessment methods for BD exposure risks have evolved from early animal and limited human studies to advanced exposure-response modelling with comprehensive quantitative data. The objec- tive of this study is to explore the nuances of exposure-response modelling, investigating how various statistical methods have influenced the quan- tification of exposure-response relationships.

Although this study was not conducted as a formal systematic review, a search was performed in Medline/Pubmed to identify all human studies on leukemia risk assessment for BD exposure. This search included articles written in English. The electronic search spanned from inception of records until July 23, 2023, using the search term: "butadiene AND (leukaemia OR leukemia OR myeloid OR lymphoid)" and was restricted to human species. Focusing on the synthetic styrene-butadiene rubber (SBR) industry cohort study conducted by the University of Alabama at Birmingham, USA, this review evaluates various statistical models and factors influenc- ing exposure-response modelling.

Peak exposures to BD may be more influential in the dose-response relationship than cumulative or long-term exposure. The authors recommend utilizing β-coefficients derived from the latest SBR study update, employing Cox proportional hazard modelling, non-lagged and non-transformed cumulative BD exposure, and adjusting for age and peak BD exposure. The study reveals that statistical model selection has a limited impact on the calculated dose-response effects. The significant variation in estimated cancer mortality values arises from additional assumptions needed for metrics like the excess leukemia risk or the occupational BD effective concentration.

In con- clusion, this study provides insights into exposure-response modelling for BD exposure and leukemia mortality, highlighting the importance of peak exposures. The recommended statistical approach offers a reliable basis for regulatory risk assessment and public health population metrics. Int J Occup Med Environ Health. 2024;37(3):300-10.

To evaluate exposure-response between 1,3-butadiene, styrene and lymphohaematopoietic cancers in an updated cohort of workers at six North American plants that made synthetic rubber polymers.

Employees were followed from 1943 through 2009 to determine mortality outcomes. Cox regression analyses estimated rate ratios (RRs) and 95% CIs by quartile of cumulative exposure to butadiene or styrene, measured in parts per million-years (ppm-years), and exposure-response trends for all leukaemia, lymphoid leukaemia, myeloid leukaemia, acute myeloid leukaemia, non-Hodgkin's lymphoma (NHL), multiple myeloma and all B-cell malignancies.

Among 21 087 workers, adjusted RRs for butadiene and all leukaemia (132 deaths) rose with increasing exposure, with an RR of 2.53 (95% CI 1.37 to 4.67) in the highest exposure quartile (≥363.64 ppm-years), and the exposure-response trend was statistically significant for all leukaemia (p=0.014) and for lymphoid leukaemia (52 deaths, p=0.007). Styrene exposure-response trends for all leukaemia and lymphoid leukaemia were less consistent than those for butadiene. Cumulative exposures to butadiene and styrene were not associated consistently with myeloid leukaemias or the B-cell malignancies, NHL and multiple myeloma.

We confirmed a positive exposure-response relationship between butadiene and all leukaemia among workers, most of whom had coexposure to styrene. Results supported an association between butadiene and lymphoid leukaemia, but not myeloid leukaemia, and provided little evidence of any association of butadiene or styrene exposures with major subtypes of B-cell malignancies other than lymphoid leukaemia, including NHL and multiple myeloma.

- To evaluate exposure-response relationships between 1,3-butadiene and styrene and selected diseases among synthetic rubber polymer workers.

- 21,087 workers (16,579 men; 4508 women) were followed from 1943 through 2009 to determine mortality outcomes. Cox regression models estimated rate ratios (RRs) and 95% confidence intervals (CIs) by quartile of cumulative exposure to butadiene or styrene and exposure-response trends for cancers of the bladder, lung, kidney, esophagus and pancreas, and for all nonmalignant respiratory disease (NMRD), chronic obstructive pulmonary disease (COPD) and pneumonia.

- Bladder cancer RRs were 2.13 (95% CI = 1.03 to 4.41) and 1.64 (95% CI = 0.76 to 3.54) in the highest quartiles of cumulative exposure to butadiene and styrene, respectively, and exposure-response trends were positive for both monomers (butadiene, trend p = 0.001; styrene, trend p = 0.004). Further analyses indicated that the exposure-response effect of each monomer on bladder cancer was demonstrated clearly only in the subgroup with high cumulative exposure (at or above the median) to the other monomer. Lung cancer was not associated with either monomer among men. Among women, lung cancer RRs were above 1.0 in each quartile of cumulative exposure to each monomer, but exposure-response was not seen for either monomer. Male workers had COPD RRs slightly above 1.0 in each quartile of cumulative exposure to each monomer, but there was no evidence of exposure-response among the exposed. Monomer exposure was not consistently associated with COPD in women or with the other cancer outcomes.

- This study found a positive exposure-response relationship between monomer exposures and bladder cancer. The independent effects of butadiene and styrene on this cancer could not be delineated. In some analyses, monomer exposure was associated with lung cancer in women and with COPD in men, but inconsistent exposure-response trends and divergent results by sex do not support a causal interpretation of the isolated positive associations.

Temperature dependent rate coefficients for the reaction of Cl atom with 1,3-butadiene were measured over the temperature range 269-363 K relative to its reaction with isoprene and 1-pentene. Theoretical calculations were performed for the title reaction using CVT/SCT in combination with CCSD(T)/6-31+G (d,p)//MP2/6-311+G(2df,2p) level of theory, to complement our experimental measurements. The test molecule would survive for 1 h in the atmosphere, and therefore, it can be considered as a very short-lived compound. 1,3-Butadience cannot contribute to global warming as it is very short-lived. However, 4 ppm of ozone is estimated to be formed by the test molecule, which can be considered to be reasonably significant.

Hepatocellular carcinoma (HCC) is the most common type of liver cancer. The main risk factors for HCC are alcoholism, hepatitis B virus, hepatitis C virus, nonalcoholic steatohepatitis, obesity, type 2 diabetes, cirrhosis, aflatoxin, hemochromatosis, Wilson's disease and hemophilia. Occupational exposure to chemicals is another risk factor for HCC. Often the relationship between occupational risk and HCC is unclear and the reports are fragmented and inconsistent. This review aims to summarize the current knowledge regarding the association of infective and non-infective occupational risk exposure and HCC in order to encourage further research and draw attention to this global occupational public health problem.

Previously, our laboratory has shown that hydroxymethylvinyl ketone (HMVK), a Michael acceptor oxidation product of the 1,3-butadiene metabolite, 3-butene-1,2-diol, readily reacts with hemoglobin at physiological conditions and that mass spectrometry of trypsin-digested peptides suggested adduct formation with various nucleophilic amino acids. In the present study, we characterized reactions ofHMVK (3 mM) with three model nucleophilic amino acids (6 and/or 15 mM): N-acetyl-L-cysteine (NAC),L-valinamide, and N-acetyl-L-lysine (NAL). NAC was the most reactive toward HMVK followed by L-valinamide and NAL. HMVK incubations with each amino acid at pH 7.4 and 37 degrees C resulted in the formation of a mono-Michael adduct. In addition, HMVK incubated with NAL gave rise to two additional bis-Michael adducts characterized by LC/MS, LC/MS/MS, 1H NMR, and 1H-detected heteronuclear single quantum correlation. The relative ratios of areas of NAL monoadduct (adduct 1) and diadducts (adducts 2 and 3) at 6 h were 49, 21, and 30% of total product area, respectively. The formation of adduct 2 was dependent upon the presence of both adduct 1 and HMVK, whereas the formation of adduct 3 was dependent upon the presence of adduct 2 only. Monoadducts were formed by a Michael addition reaction of one HMVK moiety with nucleophilic amino acid, whereas NAL diadducts were products of two Michael addition reactions of two HMVK moieties followed by enolization and formation of an octameric cyclic product. NAL diadduct (adduct 3) was formed by loss of a water molecule from adduct 2 followed by autoxidation of one of the hydroxy groups, yielding a diketone conjugated system. Collectively, our results provide strong evidence that HMVK can react with various nucleophilic residues and form different types of adducts, suggesting that a variety of proteins may be subjected to these modifications, which could result in loss of protein function.

This study assessed personal exposure to 1,3-butadiene (BD) and styrene in three plants manufacturing styrene-butadiene (SB) copolymers. Air samples were collected from the breathing zone of 28 workers over 4 months in three SB plants using diffusive samplers. The total number of samples was 885 with the number of samples per participant varying from 19 to 39. Samples were collected by use of 3M 3500 passive monitors and analyzed with a gas chromatograph (GC). Sampling proved to be simple and inexpensive and laboratory analysis of BD could detect 0.01 and 0.007 part per millions (ppm) of styrene in the 8h samples. In the case of BD, 624 samples were below the limit of quantification (LOQ), 240 samples were between the LOQ and 1 ppm, and 21 samples exceeded the threshold limit value (TLV). In the case of styrene 336 samples were below the LOQ, 548 samples were between the LOQ and 20 ppm. The TLV was exceeded once. The data gives a comprehensive picture of personal exposure of workers in modern SB latex manufacturing plants. The study illustrates also how the new TLV of BD is being implemented.

This study evaluated the association between exposure to several chemicals and mortality from lymphohematopoietic cancer (LHC) among 16,579 synthetic rubber industry workers who were followed up from 1943 to 1998.

Poisson regression analyses examined LHC rates in relation to butadiene, styrene, and DMDTC exposure. Models provided maximum likelihood estimates of the relative rate for the contrast between categories of one agent, adjusting for other agents and for additional potential confounders.

Cumulative exposure to 1,3-butadiene was associated positively with all leukemia (relative rates of 1.0, 1.4, 1.2, 2.9, and 3.7, respectively, for exposures of 0, >0 to <33.7, 33.7 to <184.7, 184.7 to <425.0, and 425.0+ ppm-years), chronic myelogenous leukemia and to a lesser extent with chronic lymphocytic leukemia. Adjusting for styrene and DMDTC attenuated these associations. After controlling for butadiene, neither styrene nor DMDTC displayed a consistent exposure-response trend with all leukemia, chronic myelogenous leukemia, or chronic lymphocytic leukemia.

This study found a positive association between butadiene and leukemia that was not explained by exposure to other agents examined.

Environment pollution by 1,3-butadiene had considerably increased in Japan. The main cause of the pollution is the automotive exhaust gas, and leaks from factories, smoking, and burning of rubber and plastic products are considered to be minor sources. The object of this study was to determine the contamination levels of airborne 1,3-butadiene in factories processing rubber and plastics containing 1,3-butadiene. The concentrations of airborne 1,3-butadiene were measured in 21 plants (10 rubber processing plants and 11 plastics processing plants) in Osaka. 1,3-Butadiene in air was collected for 10 minutes with a charcoal tube and a portable small pump adjusted to a 250 ml/min flow rate. In each plant, indoor air samples at five points and an outdoor air sample at one point outside the plant were collected. The samples were subjected to gas chromatography/mass spectrometry after thermal desorption from the charcoal. The concentrations of airborne 1,3-butadiene in the rubber processing plants and the plastics processing plants were 0.14-2.20 micrograms/m3 (geometric mean: 0.48 microgram/m3) and 0.23-4.51 micrograms/m3 (geometric mean: 0.80 microgram/m3), respectively. In all plants examined, indoor 1,3-butadiene concentrations were higher than the outdoor concentrations around the plants. Therefore, 1,3-butadiene was considered to arise from the processing of rubber or plastics, but the indoor 1,3-butadiene concentrations were much lower than the PEL-TWA (1 ppm = 2.21 mg/m3) of OSHA and the TLV-TWA (2 ppm) of ACGIH. The concentrations in the plants with closed room conditions without ventilation were higher than the concentrations in the other plants. It was suggested that ventilation affected the 1,3-butadiene concentration in the plants.

1,3-Butadiene (BD), a suspected human carcinogen, is used as the raw material in industries to make synthetic butyl rubber and plastics. Simulation models using experimental animal data have shown that physiologic factors play an important role in the kinetic behavior of BD. However, human data are limited. The aim of this inhalation study was to identify influential human physiologic factors in the respiratory uptake of BD. We recruited 133 healthy volunteers in Boston, Massachusetts, into this study and tested them under an approved human subjects protocol. Each subject was exposed to 2 ppm (4.42 mg/m3) BD for 20 min, followed by purified air for another 40 min. Five exhaled breath samples collected during exposure were used to determine the respiratory uptake of BD, which was defined as absorbed BD (micrograms) per kilogram of body weight during exposure. Although subjects were given identical administered doses (40 ppm x min), there was a wide range of uptake, 0.6-4.9 microg/kg. Of the studied physiologic factors, the blood:air partition coefficient and alveolar ventilation were most significant in determining the respiratory uptake (p < 0.001 for each). In addition, in the multiple regression analysis, females had significantly higher respiratory uptake of BD than males on a weight basis. For all subjects, increasing age and cigarette smoking led to significantly decreased respiratory uptake of BD. The results of this human study are consistent with previous kinetic simulations and animal studies. The findings also suggest that interindividual variation in human physiologic factors that affect the exposure-internal dose relationship should be considered while also exploring exposure-disease associations in future epidemiologic research.

1,3-Butadiene, isoprene (2-methyl-1,3-butadiene), and chloroprene (2-chloro-1,3-butadiene) are high-production-volume chemicals used mainly in the manufacture of synthetic rubber. Inhalation studies have demonstrated multiple organ tumorigenic effects with each of these chemicals in mice and rats. Sites of tumor induction by these epoxide-forming chemicals were compared to each other and to ethylene oxide, a chemical classified by the National Toxicology Program (NTP) and by the International Agency for Research on Cancer (IARC) as carcinogenic to humans. For this group of chemicals, there are substantial species differences in sites of neoplasia; neoplasia of the mammary gland is the only common tumorigenic effect in rats and mice. Within each species, there are several common sites of tumor induction; these include the hematopoietic system, circulatory system, lung, liver, forestomach, Harderian gland, and mammary gland in mice, and the mammary gland and possibly the brain, thyroid, testis, and kidney in rats. For studies in which individual animal data were available, mortality-adjusted tumor rates were calculated, and estimates were made of the shape of the exposure-response curves and ED10 values (i.e. exposure concentrations associated with an excess risk of 10% at each tumor site). Most tumorigenic effects reported here were consistent with linear or supralinear models. For chloroprene and butadiene, the most potent response was for the induction of lung neoplasms in female mice, with ED10 values of 0.3 ppm. Based on animal cancer data, isoprene and chloroprene are listed in the NTP's Report on Carcinogens (RoC) as reasonably anticipated to be a human carcinogen. Butadiene is listed in the RoC as known to be a human carcinogen 'based on sufficient evidence of carcinogenicity from studies in humans, including epidemiological and mechanistic information', with support from experimental studies in laboratory animals. Epidemiology data for isoprene and chloroprene are not considered adequate to evaluate the potential carcinogenicity of these agents in humans.

This is a cohort mortality study of 2800 male workers employed at least 6 months between 1943 and 1996 at a 1,3-butadiene monomer production facility. Earlier analyses of mortality for this cohort found statistically significant deficits for the 'all causes of death' category, and a lower than expected mortality for most leading causes of death. Past analyses also showed a significant elevation for deaths from cancers of the lymphohematopoietic system that was mainly due to an increase in deaths from lymphosarcoma. The purpose of this update was to examine the patterns of mortality through the end of 1999, for five additional years of follow-up. Persons who had become eligible between the last cohort update and April 1996 were added. Cohort membership was closed after April 1996 due to the sale of the facility. A total of 1422 deaths through December 1999 were identified, giving over 200 more deaths than in the last report on this aging cohort. The standardized mortality ratio (SMR) for all causes of death was 89 [95% confidence interval (95% CI) =84-94], which is statistically significantly low, and that for all malignant neoplasms was 90 (95% CI=81-101). The SMR for all lymphohematopoietic cancers (LHC) was 141 (95% CI=105-186) and is statistically significant. The SMR for leukemia was 129 (95% CI=77-204) and for non-Hodgkin's lymphoma (NHL), 148 (95% CI=89-231). The LHC elevations again were found only in workers first employed before 1950 and, in the group with the highest potential for exposure to butadiene, the elevations were highest in the short-term workers. Survival analyses were performed for all LHC [International Classification of Diseases (ICD) codes 200-209], NHL (ICD codes 200, 202), and leukemia (ICD codes 204-207) using an estimate of cumulative butadiene exposure as a time-dependent explanatory variable defined as a combination of job exposure class, calendar time, and length of time in job. The relative risks for the above causes of death were essentially 1.0, suggesting that there was no increase in risk with increasing butadiene exposure.

Butadiene epidemiologic research has focused primarily on one cohort of workers in the North American styrene-butadiene rubber (SBR) industry and on the largest cohort of workers in the United States butadiene monomer industry. The most recent studies of these populations are characterized by carefully enumerated study populations, extremely long and high quality mortality follow-up, accurate job categorizations, detailed exposure assessments, and comprehensive statistical analyses. Leukemia was clearly associated with increasing estimated butadiene exposure in the SBR study, but not in the monomer industry study. This has lead to hypotheses about exposure differences between these two industries and the presence of co-factors or confounders in the SBR industry. Research presented at this symposium should shed some light on these hypotheses. The chloroprene epidemiologic literature, on the other hand, is in an early stage of development. The existing studies are limited by poor exposure characterization, lack of control of potential confounding factors, incompleteness in cohort enumeration, short follow-up periods, and small numbers of cancer cases. The state of the science for chloroprene would be advanced by arranging more comprehensive studies than those that have been conducted to date.

1,3-Butadiene was included in the second list of Priority Substances to be assessed under the Canadian Environmental Protection Act. Potential hazards to human health were characterized on the basis of critical examination of available data on health effects in experimental animals and occupationally exposed human populations, as well as information on mode of action. Based on consideration of all relevant data identified as of April 1998, butadiene was considered highly likely to be carcinogenic to humans, and likely to be a somatic and germ cell genotoxicant in humans. In addition, butadiene may also be a reproductive toxicant in humans. Estimates of the potency of butadiene to induce these effects have been derived on the basis of quantitation of observed exposure-response relationships for the purposes of characterization of risk to the general population in Canada exposed to butadiene in the ambient environment.

This study evaluated relations between exposure to 1,3-butadiene (BD), styrene (STY) and dimethyldithiocarbamate (DMDTC) and mortality from leukemia among synthetic rubber industry workers. Subjects were 13130 men employed for at least 1 year during 1943-1991 at any of six plants that manufactured synthetic rubber. Death certificates and medical records identified workers with leukemia. Cumulative exposure estimates were based on plant- and time period-specific process and task characteristics, linked to subjects' work histories. Poisson regression estimated relative rates (RRs) for workers exposed to each agent compared to unexposed workers. Leukemia (N=59) was positively associated with BD ppm-years (RRs of 1.0, 1.2, 2.0 and 3.8, for exposures of 0, >0-<86.3, 86.3-<362.2 and 362.2+ ppm-years; only the RR for the highest exposure category was statistically significant), STY ppm-years (RRs of 1.0, 1.2, 2.3 and 3.2, for exposures of 0, >0-<20.6, 20.6-<60.4 and 60.4+ ppm-years; only the RR for the highest exposure category was statistically significant) and DMDTC mg-years/cm (RRs of 1.0, 2.3, 4.9 and 2.9, for 0, >0-<566.6, 566.6-<1395.1 and 1395.1+ mg-years/cm; the RR for each non-zero exposure category was statistically significant) after adjusting for age and years since hire. After further adjusting each agent-specific set of RRs for the other two agents, a positive but imprecise relation remained for BD and DMDTC but not for STY. The association with BD was stronger for ppm-years due to exposure intensities >100 ppm than for ppm-years due to lower concentrations. BD and DMDTC, but not STY, were positively associated with leukemia in multivariable analyses. The independent effect of each agent was difficult to evaluate because of correlations with other agents and imprecision.

This three-part study is an update of a previous report that examined the mortality, morbidity, and hematological data of employees from a petrochemical facility in Texas who had potential exposure to 1,3-butadiene monomer. The first part describes the updated cause-specific mortality of 614 workers. Vital status for each cohort member was ascertained through 1998, a 9-year extension of the previous study. The second part is an examination of the morbidity experience of cohort members who were still working during 1992-1998, including 289 of the 614 mortality cohort members. The third part is an evaluation of the hematological results from routine health surveillance and/or medical examinations. Approximately 430 of the 614 employees who had complete blood count (CBC) data as of December 1999 were included in the hematological evaluations. The most recent examination containing CBC data was used and compared with similar data for over 2600 other employees from this facility. Overall mortality during the follow-up period, 1948-1998, was significantly lower than for the local comparison population (standardized mortality ratio (SMR) of 0.55 with a 95% confidence interval (CI) of 0.42-0.70). Mortality for all cancer was also significantly lower (SMR, 0.57; 95% CI, 0.32-0.92). Mortality for all lymphohematopoietic cancer was about the same as the comparison population (SMR, 1.06; 95% CI, 0.22-3.11). None of the cause-specific morbidity was in excess compared with an internal comparison group. There were no differences in the distribution or mean values of hematological variables (e.g. white blood cells, red blood cells, hemoglobin, platelets, mean corpuscular volume) between the butadiene cohort and the comparison group, or between a subgroup of workers in jobs with the highest potential for butadiene exposure (i.e. shipping) and the rest of the butadiene cohort. The findings of this study suggest that the butadiene exposure at this facility in the last 20 years does not pose a health hazard to employees.

1,3-Butadiene is a widely used industrial chemical and common environmental pollutant that has been associated with increased risks of leukemias and lymphomas. Butadiene and its metabolites, 1, 2-epoxybutene (EB) and diepoxybutane (DEB), have been shown to be genotoxic in a wide variety of test organisms. The objective of this research was to evaluate techniques for the rapid detection of chromosomal alterations occurring in humans exposed to butadiene. We have used a multicolored fluorescence in situ hybridization (FISH) method and the CREST-modified micronucleus assay to detect chromosomal breakage induced by EB (10-300 microM) and DEB (0.5-10 microM) in cultured human lymphocytes. A significant dose-related increase in the formation of micronuclei was seen in lymphocytes treated with DEB at concentrations as low as 2.5 microM, but not with EB over the dose range tested. Over 80% of the micronuclei induced by DEB were CREST-negative, indicating their origin from chromosomal breakage. Multicolor FISH using two adjacent chromosome-specific probes showed a significant increase in chromosomal breakage in the 1cen-q12 region induced by DEB at concentrations as low as 2.5 microM, but not by EB. Since DEB is likely to be one of the metabolites contributing to the genotoxic effects of butadiene, the sensitivity of the tandem FISH approach to detect breakage induced by diepoxybutane indicates that this technique may be useful for monitoring chromosomal alterations in butadiene-exposed workers.

Chloroprene (2-chloro-1,3-butadiene) is a high production chemical used almost exclusively in the production of polychloroprene (neoprene) elastomer. Because of its structural similarity to 1,3-butadiene, a trans-species carcinogen, inhalation studies were performed with chloroprene to evaluate its carcinogenic potential in rats and mice. Groups of 50 male and female F344/N rats and 50 male and female B6C3F1 mice were exposed to 0, 12.8, 32 or 80 p.p.m. chloroprene (6 h/day, 5 days/week) for 2 years. Under these conditions, chloroprene was carcinogenic to the oral cavity, thyroid gland, lung, kidney and mammary gland of rats, and to the lung, circulatory system (hemangiomas and hemangiosarcomas), Harderian gland, kidney, forestomach, liver, mammary gland, skin, mesentery and Zymbal's gland of mice. Survival adjusted tumor rates in mice were fit to a Weibull model for estimation of the shape of the dose-response curves, estimation of ED10 values (the estimated exposure concentration associated with an increased cancer risk of 10%) and comparison of these parameters with those for 1,3-butadiene. Butadiene has been identified as a potent carcinogen in mice and has been associated with increased risk of lymphatic and hematopoietic cancer in exposed workers. Shape parameter values for most of the neoplastic effects of chloroprene and 1,3-butadiene were consistent with linear or supralinear responses in the area near the lowest tested exposures. The most potent carcinogenic effect of 1,3-butadiene was the induction of lung neoplasms in female mice, which had an ED10 value of 0.3 p.p.m. Since the ED10 value for that same response in chloroprene exposed mice was also 0.3 p.p.m., we conclude that the carcinogenic potency of chloroprene in mice is similar to that of 1,3-butadiene. Cancer potency of chloroprene is greater in the mouse lung than in the rat lung, but greater in the rat kidney than in the mouse kidney and nearly equivalent in the mammary gland of each species.

This study evaluated the mortality experience of workers from the styrene-butadiene rubber industry. Concerns about a possible association of 1,3-butadiene and styrene with lymphohaematopoietic, gastrointestinal, and lung cancers prompted the investigation.

A retrospective follow up study was conducted of 15,649 men employed for at least one year at any of eight North American styrene-butadiene rubber plants. Analyses used standardised mortality ratios (SMRs) to compare styrene-butadiene rubber workers' cause specific mortalities (1943-91) with those of the United States and Ontario general populations.

On average, there were 25 years of follow up per subject. The standardised mortality ratio (SMR) was 87 (95% confidence interval (95% CI) 85 to 90) for all causes of death combined and was 93 (95% CI 87 to 99) for all cancers. There was an excess of leukaemia (SMR 131, 95% CI 97 to 174), restricted to hourly workers (SMR 143, 95% CI 104 to 191). For causes of death other than leukaemia, SMRs were close to or below the null value of 100. Results by work area (process group) were unremarkable for non-Hodgkin's lymphoma, multiple myeloma, and stomach cancer. Maintenance workers had a slight increase in deaths from lung cancer, and certain subgroups of workers had more than expected deaths from cancer of the large intestine and the larynx.

This study found an excess of leukaemia that is likely to be due to exposure to butadiene or to butadiene plus other chemicals. Deaths from non-Hodgkin's lymphoma, multiple myeloma, and stomach cancer did not seem to be related to occupational exposure. The excess deaths from lung cancer among maintenance workers may be due in part to confounding by smoking, which was not controlled for, and in part to an unidentified occupational exposure other than butadiene or styrene. Increases in cancer of the large intestine and larynx were based on small numbers, did not seem to be due to exposure to butadiene or styrene, and may be chance observations.

The genotoxicity of diepoxibutane (DEB) and epoxybutene (EB), two of the main metabolites of 1,3-butadiene, was tested in the germ and somatic cells of the mouse by applying an MN assay in early spermatids, and in peripheral blood reticulocytes of a subgroup of the same animals. DEB (0.17 and 0.35 mmol/kg) and EB (0.35, 0.70 and 1.04 mmol/kg) were administered i.p. In the germ cell assay, significant increases of MN were observed after treatment of premeiotic S-phase cells with both butadiene metabolites, but DEB was shown to be more powerful than EB in the induction of chromosomal damage. A weak effect of the same compounds was also found after treatment of late spermatocytes, approaching the meiotic divisions. From the MN assay in peripheral blood reticulocytes, a statistically significant increase of the frequency of MN was detected at each dose tested for both chemicals. However, the results have again shown that DEB is much more efficient than EB in inducing chromosome damage.

This is a further update of a cohort mortality study of 2795 male workers employed at least 6 months between 1942 and 1994 at a 1,3-butadiene facility. Earlier reports on this cohort found a statistically significant deficit for all causes of death and lower than expected mortality for most leading causes of death. Prior reports noted an excess of deaths from lymphosarcoma primarily in those employed less than 10 years, first employed before 1946, and employed in jobs with the potential for daily exposure to butadiene (BD). There was a nonsignificant elevation for leukemia in persons potentially exposed to BD on an intermittent basis. The purpose of this update was to examine the patterns of mortality with four additional years of follow-up. Persons who had become eligible since the cohort was last updated through 1990 were also added. A total of 1222 deaths were identified, and death certificates were obtained for all but 20 of the deaths (1.6%). The standardized mortality ratio (SMR) for all causes of death is 88 (95% confidence interval (CI) = 83-93), and for all cancer, the SMR is 92 (95% CI = 82-104). There were 42 deaths from lymphohematopoietic cancers (LHC) with 28.6 expected (SMR = 147, 95% CI = 106-198), 9 observed vs. 4.7 expected deaths for lymphosarcoma (SMR = 191, 95% CI = 87-364), 13 observed vs. 11.5 expected deaths for leukemia (SMR = 113, 95% CI = 60-193), and 15 observed vs. 9.9 expected deaths from cancer of other lymphatic tissue (SMR = 152, 95% CI = 85-250). Subcohort analyses showed that the elevated risk of all LHC and its subcategories was restricted to persons who were first employed before 1950. As an adjunct to the SMR analyses, modeling was done using a qualitative cumulative exposure score as a time-dependent explanatory variable for, (1) all LHC (ICD 200-209); (2) lymphosarcoma (ICD 200); (3) lymphosarcoma and other lymphoma (ICD 200, 202); (4) multiple myeloma (ICD 203); and (5) leukemia (ICD 204-207). The cumulative exposure score was not significantly associated with any of these cancers. Cancer risk was found to increase with age for all of the LHC groups analyzed, except for lymphosarcoma. Similarly, cancer risk was found to increase with age-at-hire for all of the LHC groups except for multiple myeloma.

Based on the symposium on 1,-3-butadiene and isoprene at Blaine, WA, the following areas need special attention for future research: (1) discrepancies in PBPK modelling by different groups should be solved; (2) potential human target tissues (bone marrow, lymphatic tissues) should be better integrated into PBPK models; (3) the present rapid development in research on human genetic interindividual differences in 1,3-butadiene metabolism and toxicity should be supported, with the intention to determine human subgroups of differential susceptibility and to integrate this into epidemiological research; (4) further validation of past exposures in the epidemiologically studied corhorts is very desirable; (5) the question of possibly differential effects in 1,3-butadiene monomer workers and styrene-butadiene-rubber workers (lymphosarcoma?, reticulosarcoma?, leukemia?) should be resolved in future epidemiological studies; (6) potential human target tissues (bone marrow, lymphatic tissues) should be better integrated into PBPK modelling; (7) risk assessment of isoprene and, by quantitative comparison, of 1,3-butadiene in humans should consider the physiological background of endogenous isoprene production; and (8) future research on biomarkers should establish practical tools for medical surveillance of presently exposed persons.

Although 1,3-butadiene (BD) has been classified as an animal carcinogen, epidemiologic research has reported inconsistent results on the relationship between BD and lymphopoietic and other cancers in humans. This study evaluated the mortality experience of 15649 men employed for at least 1 year at any of eight North American styrene-butadiene rubber (SBR) plants. About 75% of the subjects were exposed to BD; 83% were exposed to styrene (STY). During 1943-1991, the cohort had a total of 386172 and an average of 25 person-years of follow-up, with 3976 deaths observed compared to 4553 deaths expected based on general population mortality rates (standardized mortality ratio (SMR) = 87, 95% confidence interval (CI) = 85-90). More than expected leukemia deaths occurred in the overall cohort (48 observed/37 expected, SMR = 131, CI = 97-174) and among ever hourly subjects (45/32, SMR = 143, CI = 104-191). The excess was concentrated among ever hourly subjects with 10+ years worked and 20+ years since hire (28/13, SMR = 224, CI = 149-323) and among subjects in polymerization (15/6.0, SMR = 251, CI = 140-414), maintenance labor (13/4.9, SMR = 265, CI = 141-453) and laboratories (10/2.3, SMR = 431, CI = 207-793), three areas with potential for relatively high exposure to BD or STY monomers. Some cohort sub-groups had slight increases in deaths from lymphopoietic cancers other than leukemia, but mortality patterns by race, years worked and process group within the SBR industry did not indicate a causal association with occupational exposures. These results indicate that exposures in the SBR industry cause leukemia.

In the last decade there has been in-depth research into understanding the health effects of 1,3-butadiene in humans and in animals. With increasing knowledge of metabolism, pharmacokinetics and mechanism of action studied in animals, the uncertainties in risk assessment will be lessened. Still, some data gaps exist which, if filled, will be useful for meaningful risk assessments for the general population. This paper discusses the future needs for research in both non-cancer and cancer effects.

In this paper we report DNA binding of butadiene monoepoxide, a first metabolite of 1,3-butadiene catalyzed by monooxygenases. We prepared alkylated purines as marker compounds for 32-P-postlabeling and electrochemical analysis and developed methods to measure the corresponding products. The traditional postlabeling assay was modified by incorporating a solid phase extraction column and high-performance liquid chromatography (HPLC) enrichment steps to the assay prior to labeling. The final analysis of adducted N6 adenines is based on two dimensional thin-layer chromatography (TLC) and an on-line HPLC/radioactivity analysis. The qualitative and quantitative results are based on positively identified marker compounds. Alkylated N7 guanines were released from DNA by neutral thermal hydrolysis, prepurified by HPLC, and analyzed by HPLC with a sensitive electrochemical detection procedure. By using these methods, we found alkylation of calf thymus DNA exposed to butadiene monoepoxide in vitro at adenine N6 and guanine N7 sites. Analysis of lung DNA samples from mice and rats exposed to butadiene through inhalation showed that adenine N6 adducts were formed in vivo in a dose responsive manner.