A follow-up study of synthetic rubber workers

doi:10.1016/0300-483X(96)03443-9

Toxicology

Volume 113, Issues 1–3, 28 October 1996, Pages 182-189

https://doi.org/10.1016/0300-483X(96)03443-9 Get rights and content

Abstract

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 386 172 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 ( $4532, SMR = 143, CI = 104–191$ ). The excess was concentrated among ever hourly subjects with 10 + years worked and 20+ years since hire ( $2813, SMR = 224, CI = 149–323$ ) 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.

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Cited by (162)

Short- and long-term variations, spatial analysis along with cancer health risk assessment associated with 1, 3-butadiene
2020, Atmospheric Pollution Research
Citation Excerpt :
1, 3-butadiene (BD) is among the most studied volatile organic compounds (VOCs) due to potential carcinogenic properties attributed to this air contaminant. In this context, the occupational exposure to BD can induce leukemia (Delzell et al., 1996; Arayasiri et al., 2010; Zhang et al., 2012) through mechanisms such as DNA damage (Kennedy et al., 2009; Ruchirawat et al., 2010), induction of abnormality in chromosomes and formation of DNA adducts (Zhao et al., 2000). Regarding BD, recent studies indicated a high risk of carcinogenicity both in experimental animals (Lewis et al., 2019a, 2019b) and human populations primarily because of exposure to its metabolites such as 1,2,3,4 diepoxybutane which increases the formation rate of DNA adducts (Walker et al., 2019).
In this study, spatial analysis and chronic cancer risk of ambient values of 1, 3-butadiene (BD) were investigated in the eastern USA. In addition, the temporal variation of BD was assessed in Beaumont, Texas. Both spatial and temporal analyses indicated that in addition to traffic emissions, some other sources such as forest fires and industrial activities may contribute locally to the release of BD in the atmosphere. A combined method of TBATS and Prophet was utilized for the first time for multi-seasonal decomposition of BD between 2014 and 2018 along with time series forecasting indicating the existence of an annual seasonality in daily values of BD. The time series forecasting by Prophet proved that the trend of BD is expected to decrease from 2019 to 2021 with higher values in the cold seasons in comparison with the summertime. Based on the findings of both deterministic and probabilistic health risk assessment (PRA), the children were exposed to a higher risk due to inhalation of BD. For instance, regarding PRA, the respective median, mean and maximum risk values for the children were 6.72 × 10⁻⁶, 3.17 × 10⁻⁵ and 4.24 × 10⁻³, respectively demonstrating that the true risk may be higher if the uncertainty in the input parameters is taken into account. Meanwhile, with respect to the findings for the children, 42.40% of the local residents were exposed to a higher acceptable risk level of 1 × 10⁻⁵ while only 6.84% are exposed to an immediate risk greater than the threshold level of 1 × 10⁻⁴.
High throughput HPLC-ESI<sup>-</sup>-MS/MS methodology for mercapturic acid metabolites of 1,3-butadiene: Biomarkers of exposure and bioactivation
2015, Chemico-Biological Interactions
1,3-Butadiene (BD) is an important industrial and environmental carcinogen present in cigarette smoke, automobile exhaust, and urban air. The major urinary metabolites of BD in humans are 2-(N-acetyl-l-cystein-S-yl)-1-hydroxybut-3-ene/1-(N-acetyl-l-cystein-S-yl)-2-hydroxybut-3-ene (MHBMA), 4-(N-acetyl-l-cystein-S-yl)-1,2-dihydroxybutane (DHBMA), and 4-(N-acetyl-l-cystein-S-yl)-1,2,3-trihydroxybutyl mercapturic acid (THBMA), which are formed from the electrophilic metabolites of BD, 3,4-epoxy-1-butene (EB), hydroxymethyl vinyl ketone (HMVK), and 3,4-epoxy-1,2-diol (EBD), respectively. In the present work, a sensitive high-throughput HPLC–ESI^–-MS/MS method was developed for simultaneous quantification of MHBMA and DHBMA in small volumes of human urine (200 μl). The method employs a 96 well Oasis HLB SPE enrichment step, followed by isotope dilution HPLC–ESI⁻-MS/MS analysis on a triple quadrupole mass spectrometer. The validated method was used to quantify MHBMA and DHBMA in urine of workers from a BD monomer and styrene-butadiene rubber production facility (40 controls and 32 occupationally exposed to BD). Urinary THBMA concentrations were also determined in the same samples. The concentrations of all three BD-mercapturic acids and the metabolic ratio (MHBMA/(MHBMA + DHBMA + THBMA)) were significantly higher in the occupationally exposed group as compared to controls and correlated with BD exposure, with each other, and with BD-hemoglobin biomarkers. This improved high throughput methodology for MHBMA and DHBMA will be useful for future epidemiological studies in smokers and occupationally exposed workers.
A comprehensive review of occupational and general population cancer risk: 1,3-Butadiene exposure-response modeling for all leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, myeloid neoplasm and lymphoid neoplasm
2015, Chemico-Biological Interactions
Excess cancer risks associated with 1,3-butadiene (BD) inhalation exposures are calculated using an extensive data set developed by the University of Alabama at Birmingham (UAB) from an epidemiology study of North American workers in the styrene butadiene rubber (SBR) industry. While the UAB study followed SBR workers, risk calculations can be adapted to estimate both occupational and general population risks.
The data from the UAB SBR study offer an opportunity to quantitatively evaluate the association between cumulative exposure to BD and different types of cancer, accounting for the number of tasks involving high-intensity exposures to BD as well as confounding associated with the exposures to the multiple other chemicals in the SBR industry. Quantitative associations of BD exposure and cancer, specifically leukemia, can be further characterized by leukemia type, including potential associations with acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myelogenous leukemia (CML), and the groups of lymphoid and myeloid neoplasms. Collectively, these multiple evaluations lead to a comprehensive analysis that makes use of all of the available information and is consistent with the risk assessment goals of the USEPA and other regulatory agencies, and in line with the recommendations of the USEPA Science Advisory Board. While a range of cancer risk values can result from these multiple factors, a preferred case for occupational and general population risk is highlighted.
Cox proportional hazards models are used to fit exposure–response models to the most recent UAB data. The slope of the model with cumulative BD ppm-years as the predictor variable is not statistically significantly greater than zero for CML, AML, or, when any one of eight exposure covariates is added to the model, for all leukemias combined. The slope for CLL is statistically significantly different from zero. The slope for myeloid neoplasms is not statistically significantly greater than zero while the slope for lymphoid neoplasms is statistically significantly greater than zero.
The excess risk for the general population is largest for lymphoid neoplasms. The best estimates of the environmental concentrations (ECs) associated with an excess risk of 1/100,000 by age 70 years for lymphoid neoplasms, all leukemias, and CLL are EC(1/100,000)’s equal to 0.06, 0.16 and 0.38 ppm, respectively. The best estimates of the occupational BD exposure from 20 to 65 years of age associated with an excess risk of 1/10,000 by age 70 years for lymphoid neoplasms, all leukemias, and CLL are the EC(1/10,000)’s of 2.7, 7.3 and 15.1 ppm, respectively.
1,3-Butadiene, styrene and lymphohematopoietic cancer among male synthetic rubber industry workers - Preliminary exposure-response analyses
2015, Chemico-Biological Interactions
Citation Excerpt :
Lagging exposure had little impact on the magnitude of the association. Overall, the results for men in the present update are similar to those reported previously [4] and are consistent with our earlier research [10,11,13,34,35]. In addition, the present results for leukemia, insofar as they indicate a positive association, are consistent with studies of BD polymer workers performed by other investigators [27–29,33].
We updated the mortality experience of North American synthetic rubber industry workers to include follow-up from 1944 through 2009, adding 11 years of mortality data to previous investigations. The present analysis used Cox regression to examine the exposure-response relationship between 1,3-butadiene (BD) and styrene (STY) parts per million (ppm)-years and leukemia (N = 114 deaths), non-Hodgkin lymphoma (NHL) (N = 89) and multiple myeloma (MM) (N = 48). A pattern of largely monotonically increasing rate ratios across deciles of BD ppm-years and a positive, statistically significant exposure-response trend were observed for BD ppm-years and leukemia. Using continuous, untransformed BD ppm-years the regression coefficient (β) adjusted only for age was 2.6 × 10⁻⁴ (p < 0.01); the regression coefficient adjusted for age, year of birth, race and plant was 2.9 × 10⁻⁴ (p < 0.01). STY ppm-years also displayed a positive exposure-response association with leukemia. STY and BD were strongly correlated, and the separate effects of these two agents could not be estimated. For NHL, a pattern of approximately monotonically increasing rate ratios across deciles of exposure was seen for STY but not for BD; the test of trend was statistically significant in one of five models that used different STY exposure metrics and adjusted for age and other covariates. BD ppm-years and STY ppm-years were not associated with MM. The present analyses indicated a positive exposure-response relationship between BD cumulative exposure and leukemia. This result along with other research and biological information support an interpretation that BD causes leukemia in humans. STY exposure also was positively associated with leukemia, but its independent effect could not be delineated because of its strong correlation with BD, and there is no external support for a STY-leukemia association. STY, but not BD, was associated positively with NHL. The interpretation of this result is uncertain because the exposure-response data were statistically imprecise and because consistent support for causality from other studies is lacking. The current study provides no support for an association between BD or STY and MM.
Quantitative risk assessment of exposures to butadiene in EU occupational settings based on the University of Alabama at Birmingham epidemiological study
2013, Regulatory Toxicology and Pharmacology
The excess risks due to 1,3-butadiene (BD) inhalation in EU occupational settings are quantified for leukemia, AML, CLL, CML, lymphoid neoplasms, and myeloid neoplasms. The most recent data from the University of Alabama at Birmingham epidemiological study of North American workers in the styrene-butadiene rubber industry are modeled.
The number of high-intensity tasks (HITs) and other exposure covariates may be more important predictors than cumulative BD ppm-years alone. For example, all of the 71 leukemia decedents in the UAB study who were exposed to BD had some BD HITs. None of the 1192 exposed workers without BD HITs had leukemia mortalities.
The authors’ best estimate (consolidated over all endpoints) of the average occupational BD exposure concentration for 45 years of exposure starting at age 20 corresponding to an added risk of 1/10,000 by age 70 is 7.2 ppm.
Cumulative BD ppm-years is not statistically significantly associated with CML, AML, or myeloid neoplasms or (after any one of eight exposure covariates is included in the modeling) leukemia. The statistical significance of the slopes for leukemia, CLL, and lymphoid neoplasms unadjusted for covariate effects disappears when modeling is restricted to person years with less than 200 cumulative BD ppm-years.
Association of Urinary N7-(1-hydroxyl-3-buten-1-yl) Guanine (EB-GII) Adducts and Butadiene-Mercapturic Acids with Lung Cancer Development in Cigarette Smokers
2024, Chemical Research in Toxicology

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A follow-up study of synthetic rubber workers

Abstract

Exp. Pathol.

Comput. Biomed. Res.

Mortality among workers engaged in the development or manufacture of styrene-based products—an update

Scand. J. Work Environ. Health

Exposure to butadiene and lymphatic and hematopoietic cancer

Epidemiology

Cancer mortality among workers at a butadiene production facility

Survey of mortality among employees engaged in the manufacture of styrene and polystyrene at the BASF Ludwigshafen works

Scand. J. Work Environ. Health

Mortality of styrene production, polymerization and processing workers at a site in northwest England

Scand. J. Work Environ. Health

Cancermortality in an international cohort of workers exposed to styrene