Cancer mortality in an international cohort of reinforced plastics workers exposed to styrene: a reanalysis.

OBJECTIVE: To investigate the carcinogenicity of styrene by reanalysing data from a previous international cohort study of workers in the reinforced plastics industry. METHODS: Mortality from cancers of prior interest was analysed with more detailed consideration of exposure-response relations and an updated classification of leukaemias and lymphomas in data from a previous international cohort study of 37 021 reinforced plastics workers exposed to airborne styrene. RESULTS: Increased mortality from non-Hodgkin's lymphoma (NHL) was associated with the mean level of exposure to styrene in air (relative risk (RR) 2.31, 95% CI 1.29 to 4.12 per 100 ppm), but not with cumulative styrene exposure. Similar associations with mean exposure were observed for the oesophagus (RR 2.44, 95% CI 1.11 to 5.36 per 100 ppm) and pancreas (RR 1.89, 95% CI 1.17 to 3.09). Oesophageal cancer mortality was also associated with cumulative styrene exposure lagged 20 years (RR 1.16, 95% CI 1.03 to 1.31). No other cancer, including lung cancer, was associated with any indicator of styrene exposure. CONCLUSION: This reanalysis does not substantially change the conclusions of the original study with respect to NHL or lung cancer but new evidence concerning cancers of the oesophagus and pancreas merits further investigation.

Eosinophilic bronchitis caused by styrene

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Environmental-sanitary risk analysis procedure applied to artificial turf sports fields.

Owing to the extensive use of artificial turfs worldwide, over the past 10 years there has been much discussion about the possible health and environmental problems originating from styrene-butadiene recycled rubber. In this paper, the authors performed a Tier 2 environmental-sanitary risk analysis on five artificial turf sports fields located in the city of Turin (Italy) with the aid of RISC4 software. Two receptors (adult player and child player) and three routes of exposure (direct contact with crumb rubber, contact with rainwater soaking the rubber mat, inhalation of dusts and gases from the artificial turf fields) were considered in the conceptual model. For all the fields and for all the routes, the cumulative carcinogenic risk proved to be lower than 10(-6) and the cumulative non-carcinogenic risk lower than 1. The outdoor inhalation of dusts and gases was the main route of exposure for both carcinogenic and non-carcinogenic substances. The results given by the inhalation pathway were compared with those of a risk assessment carried out on citizens breathing gases and dusts from traffic emissions every day in Turin. For both classes of substances and for both receptors, the inhalation of atmospheric dusts and gases from vehicular traffic gave risk values of one order of magnitude higher than those due to playing soccer on an artificial field.

Utilización de marcadores genéticos de la CYP2E1 en la valoración de riesgos de exposición laboral a estireno mediante control biológico / Use of genetic markers for CYPE1 in the assessment of risks through occupational exposure to styrene using biologic controls

Hemos estudiado la utilidad del genotipado y fenotipado de la enzima CYP2E1 para la evaluación del riesgo de exposición laboral a estireno, correlacionando los datos obtenidos con los indicadores biológicos habituales en programas de Salud Laboral (ácidos mandélico y fenilglioxílico, principales metabolitos urinarios del estireno). Se examinaron 49 trabajadores con exposición conocida a estireno y un grupo control, determinándose mARN de CYP2E1 en sangre y polimorfismos de la enzima en muestras de mucosa oral. Nuestros resultados muestran que el efecto combinado del fenotipo de CYP2E1 y del genotipo de los alelos CYP2E1*5B y CYP2E1*6 puede explicar en parte la variabilidad en la excreción urinaria de metabolitos del estireno. La técnica de obtención de material biológico a partir de la mucosa oral puede ser de interés en el ámbito laboral (AU)

We have studied the usefulness of geno and phenotyping of the enzyme CYP2E1 for the assessment of risk through occupational exposure to styrene and correlated the results achieved with the habitual biologic markers in Occupational Health programmes (mandelic and phenylglyoxylic acids, the main urinary metabolites of styrene). The study group comprised 49 workers with known exposure to styrene and a control group; CYP2E1 mRNA in blood and enzyme polymorphisms in samples of the oral mucosa were assessed. Our results show that the combined affects of CYP2E1 phenotype and of the CYP2E1*5B and CYP2E1*6 allele genotype may in part explain the variability in the urinary excretion of styrene metabolites. The sampling technique for biologic material from the oral mucosa may be useful in the occupational environment (AU)

A follow-up study of mortality among women in the North American synthetic rubber industry.

OBJECTIVE: To evaluate mortality from cancer and other diseases among 4863 women employed at eight North American styrene-butadiene rubber plants. Cancers of the lymphohematopoietic tissues, breast, and ovary were of strongest a priori interest. METHODS: Cause-specific standardized mortality ratios (SMRs) and 95% confidence intervals (CIs) were estimated. RESULTS: The observed number of deaths was approximately equal to that expected for leukemia (10 observed/13 expected), Hodgkin lymphoma (1/1.6), multiple myeloma (7/7.9), non-Hodgkin lymphoma (15/14), and cancers of the breast (72/74) and ovary (21/22). Ever-hourly women had more than expected deaths from lung (47/30, SMR = 159, CI = 117 to 211) and bladder (6/1.8, SMR = 332, CI = 122 to 723) cancers. Exposure-response analysis, done only for lung cancer, indicated no trend for butadiene or styrene. CONCLUSIONS: The observed excesses of lung and bladder cancers may be attributable to nonoccupational factors rather than to workplace exposures.

Epidemiologic studies of styrene and cancer: a review of the literature.

OBJECTIVE: To review the epidemiologic literature on styrene and cancer. METHODS: We reviewed studies of workers exposed to styrene in manufacturing and polymerization, in the reinforced plastics industry, and in styrene-butadiene rubber production. We also reviewed studies of workers monitored for styrene exposure, studies of environmental exposure, community-based case-control studies of lymphoma and leukemia, and studies of DNA adducts. Studies of workers in the reinforced plastics industry were considered more informative because of higher worker exposure and less confounding by other carcinogens. RESULTS: We found no consistent increased risk of any cancer among workers exposed to styrene. A study of reinforced plastic workers reported an association between average estimated styrene exposure and non-Hodgkin lymphoma (NHL, P = 0.05) but no trend with increasing duration of exposure. Other studies of styrene exposure and NHL found no increased risk. In two US studies of reinforced plastic workers, esophageal cancer mortality was increased, but these findings were generated in a background of multiple comparisons. Results for other cancers were unremarkable. CONCLUSIONS: The available epidemiologic evidence does not support a causal relationship between styrene exposure and any type of human cancer.

Variability in human sensitivity to 1,3-butadiene: Influence of the allelic variants of the microsomal epoxide hydrolase gene.

The carcinogenic effects of 1,3-butadiene (BD), a chemical widely used in the rubber industry, are thought to be due to its epoxide metabolites. In humans, these epoxides are detoxified predominantly by hydrolysis, a reaction mediated by the microsomal epoxide hydrolase (mEH) enzyme. The mEH gene is polymorphic and the most common mEH coding-region variants detected in human populations are the two amino acid polymorphisms Tyr113His and His139Arg. Polymorphic amino acid substitutions at residues 113 and 139 in the human mEH protein can associate in four distinct combinations: Tyr113/His139, Tyr113/Arg139, His113/His139, and His113/Arg139. In vitro studies have shown that each of these genotypes has a unique mEH protein level that can affect net mEH enzymatic activity. In the current study, we examined the relationships among the genotypes involving these two polymorphisms and the mutagenic responses associated with occupational exposure to BD. We studied 49 nonsmoking workers from two styrene-butadiene rubber facilities in southeast Texas using the autoradiographic HPRT mutant lymphocyte assay as a biomarker of genotoxic effect. We genotyped the study participants simultaneously for both polymorphisms, using a multiplex PCR assay developed in our laboratory, and the subjects were assigned to a specific group based on the predicted mEH activity associated with their genotypes (low, intermediate, and high). In the study population, 67% were exposed to low BD levels of <150 ppb (measured by personal badge dosimeters) and 33% were exposed to >150 ppb (mean 2,244 ppb). In the BD low-exposure group, the mEH genotypes had no significant effect on the HPRT variant (mutant) frequency (Vf). In the high-exposure group (BD > 150 ppb), individuals with genotypes associated with low mEH activity had a significant (P < 0.05) 3-fold increase in HPRT Vf (Vf +/- SEM = 13.95 +/- 2.15 x 10(-6)) compared to high-activity individuals (4.41 +/- 1.19 x 10(-6)), and a 2-fold increase in Vf compared to intermediate-activity individuals (6.44 +/- 2.09 x 10(-6)). Our results indicate that mEH genotypes may play a significant role in human sensitivity to the genotoxic effects of exposure to BD.

Assessment of sperm DNA integrity in workers exposed to styrene.

BACKGROUND: Occupational exposure to toxic agents may cause infertility, congenital anomalies or death in offspring, but few studies have evaluated DNA integrity in germ cells of male workers. We investigated sperm DNA integrity in individuals occupationally exposed to styrene. METHODS AND RESULTS: Semen samples were obtained from 46 male workers exposed to styrene and 27 unexposed controls (age range 18-45 years). Exposed individuals had worked for at least 2 years in the last 5 years and continuously for 6 months in factories producing reinforced plastics. The Comet assay was performed to evaluate DNA integrity in sperm, as well as semen quality analysis to assess sperm concentration and morphology. There were no differences in the results of the standard semen analysis between exposed subjects and the reference group. However, we found a significant difference (P < 0.001) in sperm DNA damage by the Comet assay between exposed subjects and the reference group. CONCLUSIONS: The Comet assay proved to be sensitive in detecting an alteration in DNA integrity in germ cells of workers exposed to styrene. This finding contributes towards the understanding of the importance of male occupational exposure within the context of genetic risk assessment in humans.

Styrene dimers and trimers affect reproduction of daphnid (Ceriodaphnia dubia).

The endocrine disruptor activity of styrene in humans and other vertebrates appears to be negligible. However, offspring numbers were reduced in Ceriodaphnia dubia bred in polystyrene cups. Styrene dimers and trimers were found to be eluted from the polystyrene cups by hexane and methanol with gas chromatography-mass spectrometry. Styrene dimers and trimers at concentrations of 0.04-1.7 microg/l affected C. dubia fertility (25% reduction after seven days), suggesting that styrenes have the potential to impair crustacean populations in the aquatic environment.

Certain styrene oligomers have proliferative activity on MCF-7 human breast tumor cells and binding affinity for human estrogen receptor.

To examine the estrogenic activities of styrene oligomers, we carried out cell proliferation assays with estrogen-sensitive MCF-7 cells and competitive binding assays to human estrogen receptor [alpha] (hER[alpha]). The styrene oligomers tested were 1,3-diphenyl propane (SD-1), 2,4-diphenyl-1-butene (SD-2), cis-1,2-diphenyl cyclobutane (SD-3), trans-1,2-diphenyl cyclobutane (SD-4), 2,4,6-triphenyl-1-hexene (ST-1), 1a-phenyl-4a-(1'-phenylethyl)tetralin (ST-2), 1a-phenyl-4e-(1'-phenylethyl)tetralin (ST-3), 1e-phenyl-4a-(1'-phenylethyl)tetralin (ST-4), 1e-phenyl-4e-(1'-phenylethyl)tetralin (ST-5), 1e,3e,5a-triphenylcyclohexane (ST-6), and 1e,3e,5e-triphenylcyclohexane (ST-7). In the MCF-7 cell proliferation assay, styrene trimers (ST-1, ST-3, ST-4, and ST-5) had the highest proliferative activities of the compounds tested. The relative potency of these chemicals was 0.0002-0.0015%, which was comparable with that of bisphenol A (0.0001-0.0025%), and their relative proliferative effect was 51-104%. Styrene dimers (SD-3 and SD-4) also significantly increased the cell yields. However, SD-1, SD-2, ST-2, ST-6, and ST-7 had insignificant proliferative activities. The competitive binding assay revealed the binding affinity of some styrene oligomers for hER[alpha]. The order of their binding potency for hER[alpha] was as follows: ST-4 > ST-2 > ST-3 > ST-5 > ST-1 > SD-3 > SD-4 > SD-2 > SD-1. ST-6 and ST-7 did not appear to bind to hER[alpha]. The present studies indicate that styrene dimers SD-3 and SD-4 and styrene trimers ST-1, ST-3, ST-4, and ST-5 have estrogenic activity on MCF-7 cells and binding affinity for hER[alpha]. These compounds might be endocrine disrupters.

Use of covalent binding in risk assessment.

Risk characterization comprises hazard identification describing the intrinsic toxic potential of a chemical, toxicokinetics, as well as the toxic mechanisms, information about dose response and exposure assessment. Compounds that induce reversible effects, which are repaired during and after exposure, are considered thresholded and allow definition of a NOEL. If damage is not repaired, the effect persists and accumulates upon repeated exposure. In such cases a NOEL cannot be determined. Biological reactive intermediates of chemicals have the potential to bind covalently to cellular macromolecules like proteins and DNA. Such interaction is not repaired completely and may persist. Thus, data on covalent binding (CB) are of qualitative and quantitative significance in the risk assessment process. Qualitatively, CB, especially with DNA and in correlation with this to proteins, is indicative for an irreversible and non-thresholded mutagenic and carcinogenic effect. Absence or presence of CB assists to differentiate between primarily genotoxic and thresholded non-genotoxic carcinogens. Quantitatively, CB is used to understand internal exposure and target dose, which is a prerequisite for species-species extrapolation, and to justify extrapolation from high dose to low dose. The reactive intermediates of ethylene, propylene and styrene have been determined in rodents and humans and modeled to predict dose responses of internal exposure. It is described in this communication that such information, together with other parameters like cell proliferation as a result of cytotoxicity, is the basis for quantitative risk assessment of human exposure to these compounds.

Porphyrin status in aluminum foundry workers exposed to hexachlorobenzene and octachlorostyrene.

The possible interference of hexachlorobenzene and octachlorostyrene (i.e., thermal byproducts from hexachloroethane in aluminum degassing) with porphyrin metabolism was investigated in exposed workers. Urine specimens from 9 male aluminum foundry workers (i.e., smelters) at 6 different companies and from 18 controls-matched for sex, age, residence, and socioeconomic status-were analyzed for total porphyrins and porphyrin isomers. Workers exposed to hexachlorobenzene and octachlorostyrene had a statistically significant increase in urinary total porphyrins, compared with controls (mean +/- standard deviation: 13.63 +/- 11.13 micromol/mol creatinine and 6.24 +/- 3.84 micromol/mol creatinine, respectively; p = .02). The authors attributed the results mainly to differences in excretion of coproporphyrins-notably coproporphyrin III. Erythrocyte uroporphyrinogen decarboxylase activity was similar in both groups. There was a high correlation between levels of hexachlorobenzene and octachlorostyrene, respectively, in plasma and urinary excretion of porphyrins; these findings, however, relied heavily on 1 subject for whom extreme values were obtained. The results indicated that occupational exposure to hexachlorobenzene and octachlorostyrene in aluminum degassing with hexachloroethane may affect porphyrin metabolism in a manner consistent with early secondary coproporphyrinuria-the first recognized step in the development of chronic hepatic porphyria. It was also noted that changes remained detectable some years after exposure ceased.

Associations between several sites of cancer and occupational exposure to benzene, toluene, xylene, and styrene: results of a case-control study in Montreal.

BACKGROUND: Except for the leukemogenic effects of benzene, there is inadequate or sparse evidence on the carcinogenicity of the most common monocyclic aromatic hydrocarbons. The purpose of this study was to generate hypotheses on associations between exposure to benzene, toluene, xylene, and styrene and various common types of cancer. METHODS: In the context of a population-based case-control study carried out in Montreal, 3,730 cancer patients (15 types of cancers, not including leukemia) and 533 population controls were interviewed, and their job histories were translated by a team of experts into occupational exposures, including benzene, toluene, xylene, and styrene. In the present analysis, exposure to these substances was compared between each case series and a control group pooling selected cancer patients and population controls, using logistic regression analysis. RESULTS: Exposure levels were low for most exposed subjects, and there was a high correlation between exposure to benzene, toluene and xylene. For most sites of cancer there was no evidence of excess risk due to these substances. However, limited evidence of increased risk was found for the following associations: esophagus-toluene, colon-xylene, rectum-toluene, rectum-xylene and rectum-styrene. CONCLUSIONS: These latter observations warrant further investigation.

Mortality from cancer and other causes of death among synthetic rubber workers.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Effects on the kidney of occupational exposure to styrene.

OBJECTIVES: To elucidate the extent of nephrotoxicity of long-term occupational exposure to styrene. METHODS: In all 10 styrene-exposed workers (employed, mean age 12.6 years) and 15 nonexposed workers were studied. Each participant collected multiple overnight and end-of-shift urine samples. The sum of the urinary concentrations of mandelic acid and phenylglyoxylic acid (MAP) was determined to assess the absorbed dose of styrene. The urinary parameters alanine aminopeptidase (AAP), beta-galactosidase (beta GAL), N-acetyl-beta-D-glucosaminidase (NAG), retinol-binding protein (RBP), and albumin (ALB) were determined to assess the effects on renal function and integrity. RESULTS: The median concentration of MAP in urine was 175 mg/g urinary creatinine (CREAT-U; range 72-496 mg/g). The 8-h time-weighted average (8-h TWA) exposure to styrene was estimated from the urinary concentration of MAP and ranged from 21 to 405 mg/m3. RBP showed a borderline correlation with the dose of styrene. ALB in end-of-shift urine samples showed a borderline correlation with the absorbed dose of styrene. CONCLUSIONS: From the borderline correlation of RBP with the dose of styrene it was concluded that there might be a slight effect on the tubuli. The borderline correlation of ALB with the dose of styrene, together with the observation that five values were above the reference limit of the laboratory, suggests an effect on this parameter.

Modeling the acute neurotoxicity of styrene.

Styrene is a widely used industrial solvent associated with acute neurotoxicity. To investigate the relationships between exposure, blood concentrations, and the appearance of neurotoxic effects, four healthy males were exposed to styrene concentrations of 5-200 ppm in four different exposure-time profiles. A digit recognition test and P300 event-related evoked potential were used to measure neurologic function. A physiologically based kinetic (PBK) model generated close predictions of measured styrene blood concentrations, in the range of 0.01-12 mg/L, from this and 21 previous studies. Simulated peak brain concentration, durationXaverage exposure, and peak exposure level were predictive of toxicity. Central nervous system effects were expected at a blood concentration near 2.4 mg/L. A standard of 20 ppm was expected to protect styrene-exposed workers from acute central nervous system toxicity under light work conditions.