Hydrocarbons, C4, steam-cracker distillate

Epidemiological data

Administrative data

Endpoint:

epidemiological data

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Human workplace investigation, published in peer reviewed literature, minor restrictions in design and/or reporting but otherwise adequate for assessment

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

reference to same study

Cross-reference 2

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Biomarkers in Czech workers exposed to 1,3-butadiene: A transitional epidemiologic study.

Author:

Albertini, R.J., Sram, R.J., Vacek, P.M., Lynch, J., Nicklas, J.A., van Sittert, N.J., Boogaard, P.J., Henderson, R.F., Swenberg, J.A., Tates, A.D., Ward, J.B., Jr., Wright, M., and et al

Year:

2003

Bibliographic source:

HEI Research Report 116.

Reference 2

Reference Type:

publication

Title:

Biomarkers for assessing occupational exposures to 1,3-butadiene

Author:

Albertini, R.J. Sram, P.M. Vacek, J. Lynch, M. Wright, J.A. Nicklas, P.J. Boogaard, R.F. Henderson, J.A. Swenberg, A.D. Tates, J.B. Ward, Jr.

Year:

2001

Bibliographic source:

Chem. Biol. Interact. 135-136, 429-453

Materials and methods

Study type:

cross sectional study

Endpoint addressed:

genetic toxicity

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

The objective of these studies was to investigate biomarkers of butadiene (BD) exposure, genotype and genotoxicity in exposed Czech workers

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

1,3-Butadiene

Cas Number:

106-99-0

Molecular formula:

C4H6

IUPAC Name:

1,3-Butadiene

Details on test material:

Analytically determined

Method

Type of population:

occupational

Ethical approval:

confirmed and informed consent free of coercion received

Details on study design:

Eighty-three male volunteers at two BD facilities in the Czech Republic participated in the study: 24 in BD monomer production, 34 in polymerization activities, and 25 plant administrative workers served as unexposed control subjects. Prior to collecting biological samples, there was a 60-day exposure assessment period, during which BD exposure level measurements were taken for both the BD-exposed and unexposed control workers. At the end of the exposure assessment period, blood and urine samples were collected. The study was conducted in a blind fashion. Random numbers were assigned to each worker, and different random numbers were independently assigned to different fractions of biological samples so that samples could not be associated with workers or each other until final codes were broken.

The following biomarkers were analysed:
(1) polymorphisms in genes involving BD metabolism, i.e., GSTM1, SGTT1, ADH2, ADH3, EH 113, EH 139 and CYP2E1 5’ promoter region, and CYP2E1 intron 6
(2) urinary concentrations of M1 and M2, the mercapturic acid metabolites of BD
(3) concentrations of HBVal, the hemoglobin adduct of epoxybutene
(4) concentrations of THBVal, the hemoglobin adduct of epoxybutene diol
(5) T-cell mutations in the HPRT gene by both the autoradiographic technique and the cloning assay with the determination of the mutation spectra
(6) chromosomal aberrations by the conventional method and by fluorescence in situ method (FISH)
(7) sister chromatid exchanges (SCE).

Exposure assessment:

measured

Details on exposure:

Personal monitors were used to assess BD exposure levels for all study subjects. Multiple, semi-randomly distributed measurements on approximately ten separate occasions for 8-hour work shifts were taken over a 60-day period for each exposed worker. The exposure assessment also included concurrent levels of benzene, toluene and styrene. Workplace area measurements were also obtained from selected sites throughout the facilities. Information about possible BD exposures before the study assessment period was obtained from workplace measurements taken by the company during the preceding five years and from personnel records of changes in worker’s jobs. Detailed employment histories for all subjects were also obtained from questionnaires, administered by trained interviewers. A series of 28 random BD measurements were taken during the exposure assessment for the unexposed control workers.

Statistical methods:

Differences among the three exposure groups for all exposure metrics and biomarkers were assessed both by ANOVA, using the Student-Newman-Keuls procedure for pairwise multiple comparisons, and by the nonparametric Kruskal-Wallis test, using Bonferroni-adjusted Mann-Whitney tests for pairwise comparisons. t-Tests and Mann-Whitney tests were used to test differences between genotypes and between smokers and non-smokers. Two-way ANOVA, with group as one factor and either genotype or smoking status as the other factor, was used to test for potential interactions between the effects of BD exposure and genotype or smoking on the biomarkers. Bivariate relations between different biomarkers and between biomarkers and exposure variables were assessed by computing Spearman correlation coefficients. Pearson correlation coefficients were also computed to assess the linearity of relations.

Results and discussion

Results:

There were 24 BD monomer production workers with a mean BD exposure of 0.29 ppm (0.64 mg/m3); 34 polymerization workers with a mean BD exposure of 0.81 ppm (1.79 mg/m3); and 25 controls with a mean BD exposure of 0.01 ppm (0.022 mg/m3). The ranges of exposures over the 60-day period were up to 1.45 ppm for the workers in the monomer production facilities and up to 4.0 ppm (8.8 mg/m3) for the workers in the polymerization facilities. BD-exposed workers had elevated M1 and M2 metabolites, HBVal and THBVal hemoglobin adduct concentrations; all significantly correlated with individual BD exposure levels, with adduct concentrations being the most highly associated. The ratio of M1/M1+M2 was approximately 0.99, indicating that the hydrolytic detoxification pathway is almost exclusively used in humans. This is supported by the hemoglobin adduct data which showed about 300- to 400-fold higher levels of THBVal than HBVal. There was no evidence of irreversible DNA mutagenicity (mutations or chromosome aberrations) related to BD exposure (either from direct measurements or from the internal markers of BD metabolism, i.e., urinary metabolites and hemoglobin adducts). HPRT mutation frequencies and chromosomal aberrations were not elevated in exposed workers compared to control workers, and showed no association with BD exposure levels. The SCE frequencies and the high frequency cells were also not related to BD exposure levels. Regression analyses showed no relationships between individual exposures (as determined by means over the 60-day period) and HPRT mutations, chromosomal aberrations or SCEs. GST polymorphism did influence BD metabolism, reflective by relative M1 and M2 metabolite concentrations in the urine, with the null genotypes being associated with lower activity in the conjugation detoxification pathways. No other endpoint was affected by genotype.

Confounding factors:

None specified

Strengths and weaknesses:

The exposure assessment was comprehensive and included co-exposures to other Volatile Organic Chemicals (benzene, styrene and toluene) present in the workplace. The 60-day exposure assessment period also accommodated the lengthy half-lives of some of the biomarkers, as well as maintaining those biomarkers that would reflect short-term exposures. Finally, the study was conducted in a blind fashion.

Any other information on results incl. tables

none

Applicant's summary and conclusion

Conclusions:

There was no association between BD exposure and mutations or cytogenetic effects in the blood of BD-exposed workers. Biomarkers of exposure (urinary metabolites and hemoglobin adducts), however, were demonstrated to be valid surrogate measures of BD exposure.

Executive summary:

A molecular epidemiology study was conducted at a BD facility in the Czech Republic in order to evaluate the use of various biomarkers of exposure and genotoxicity to BD. Eighty-three male volunteers participated in the study: 24 in BD monomer production, 34 in polymerization activities, and 25 plant administrative workers served as unexposed control subjects. Prior to collecting biological samples, there was a 60-day exposure assessment period, during which BD exposure level measurements were taken for both the BD-exposed and unexposed control workers. At the end of the exposure assessment period, blood and urine samples were collected. The study was conducted in a blind fashion. The mean BD exposures were: 0.29 ppm (0.64 mg/m³) for the BD monomer production workers; 0.81 ppm (1.79 mg/m³) for the polymerization workers; and 0.01 ppm (0.022 mg/m³) for the controls. There were no statistically significant differences in the distributions of metabolic genotypes among the three exposure groups. None of the specific genotypes showed any heightened susceptibility to BD, although some specific genotypes were associated with quantitative differences in urinary metabolite concentrations of hemoglobin adducts. There was no association between BD exposure and mutations or cytogenetic effects in the blood of BD-exposed workers. Biomarkers of exposure (urinary metabolites and hemoglobin adducts), however, were demonstrated to be valid surrogate measures of BD exposure.