hprt mutant lymphocyte frequencies in workers at a 1,3-butadiene production plant.

Abstract

1,3-Butadiene is a major industrial chemical that has been shown to be a carcinogen at multiple sites in mice and rats at concentrations as low as 6.25 ppm. Occupational exposures have been reduced in response to these findings, but it may not be possible to determine by using traditional epidemiological methods, whether current exposure levels are adequate for protection of worker health. However, it is possible to evaluate the biological significance of exposure to genotoxic chemicals at the time of exposure by measuring levels of genetic damage in exposed populations. We have conducted a pilot study to evaluate the effects of butadiene exposure on the frequencies of lymphocytes containing mutations at the hypoxanthine-guanine phosphoribosyl transferase (hprt locus in workers in a butadiene production plant. At the same time, urine specimens from the same individuals were collected and evaluated for the presence of butadiene-specific metabolites. Eight workers from areas of the plant where the highest exposures to butadiene occur were compared to five workers from plant areas where butadiene exposures were low. In addition, six subjects with no occupational exposure to butadiene were also studied as outside controls. All of the subjects were nonsmokers. An air sampling survey conducted for 6 months, and ending about 3 months before the study, indicated that average butadiene levels in the air of the high-exposure areas were about 3.5 ± 7.5 ppm. They were 0.03 ± 0.03 ppm in the low-exposure areas. Peripheral blood lymphocytes from the subjects were assayed using an autoradiographic test for hprt mutations. The weighted mean variant (mutant) frequency (Vf) (± SE) in the eight exposed subjects was 3.84(±0.70) x 106 per evaluatable cell, as compared to 1.16±(0.27) x 104 in the low-exposed and 1.03(±0.07) x 106 in the outside controls. The Vf of the low-exposed controls and the outside controls were not significantly different, but the mean frequency of mutant lymphocytes in the seven exposed subjects was significantly higher when compared to the mean Vf of the nonexposed controls (p<0.01) and the low-exposed controls (p<0.05). A single metabolite of butadiene, 1,2-dihydroxy-4-(N-acetlylcysteinyl-S) butane, was detected in the urine of all subjects. The concentration in the urine of the workers in the high-exposed group was significantly greater than in the low-exposed or nonexposed groups. The correlation between the level of the metabolite in urine and the frequency of hprt mutants was r = 0.85. The observation of an elevated Vf in the exposed subjects and the strong correlation of Vf with the level of excreted metabolite suggests that butadiene exposures under these conditions were sufficient to induce somatic cell mutations. This degree of increase in Vf is similar to what we have observed in cigarette smokers. The results available at this time indicate that current levels of occupational exposure to butadiene may not be sufficiently low to protect workers from the adverse effects that may result from exposure...

Structure of the 1,4-Bis(2‘-deoxyadenosin-N6-yl)-2S,3S-butanediol Intrastrand DNA Cross-Link Arising from Butadiene Diepoxide in the Human N-ras Codon 61 Sequence

“…A. NOE connectivity for the imino protons for the base pairs from G 2 ·C 21 to A 10 ·T 13 Reactive Metabolites of Butadiene. Table 1 Analysis of the rMD-Generated Structures of the ras61 (S,S) N 6 ,N 6 -dA Cross-Linked Adduct.…”

Lack of increased genetic damage in 1,3-butadiene-exposed Chinese workers studied in relation to EPHX1 and GST genotypes

“…To provide mechanistic information on the potential carcinogenicity of BD in humans, we [7][8][9] and others [10][11][12][13][14][15] have investigated genotoxic effects in BD-exposed workers. In a study at a polybutadiene production facility in China, we examined a broad spectrum of genotoxic and other potential effects of BD.…”

Application of integrated genetic monitoring: the optimal approach for detecting environmental carcinogens.

“…Furthermore, the biological data can be correlated with the metabolic information. The initial results of the pilot study (61) indicate that present exposure levels produced an increase in hprt variants and that this increase can be correlated with a butadiene derived urinary metabolite.…”