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In vitro and in vivo genotoxicity of 1,3-butadiene and metabolites
G T Arce1, D R Vincent, M J Cunningham
1Haskell Laboratory for Toxicology and Industrial Medicine, E. I. du Pont de Nemours & Company, Inc., Newark, DE 19714.
Abstract:
1,3-Butadiene and two major genotoxic metabolites 3,4-epoxybutene (EB) and 1,2:3,4-diepoxybutane (DEB) were used as model compounds to determine if genetic toxicity findings in animal and human cells can aid in extrapolating animal toxicity data to man. Sister chromatid exchange (SCE) and micronucleus induction results indicated 1,3-butadiene was genotoxic in the bone marrow of the mouse but not the rat. This paralleled the chronic bioassays which showed mice to be more susceptible than rats to 1,3-butadiene carcinogenicity. However, 1,3-butadiene did not induce unscheduled DNA synthesis (UDS) in the rat or mouse hepatocytes following in vivo exposure. Likewise, UDS in rat and mouse hepatocytes in vitro was not induced by EB or DEB. Salmonella typhimurium gene mutation (Ames) tests of 1,3-butadiene using strains TA1535, TA97, TA98, and TA100 and employing rat, mouse, and human liver S9 metabolic systems were barely 2-fold above background only in strain TA1535 at 30% 1,3-butadiene in air with induced and uninduced rat S9 and mouse S9 (uninduced). 1,3-Butadiene was negative in in vitro SCE studies in human whole blood lymphocytes cultures treated in the presence of rat, mouse, or human liver S9 metabolic activation. In general, 1,3-butadiene is genotoxic in vivo but is a weak in vitro genotoxin.
Insights
1,3-Butadiene is genotoxic in vivo, particularly in mice, but shows weak genotoxicity in vitro. Its metabolites, epoxybutene and diepoxybutane, did not induce DNA synthesis in liver cells, suggesting limited in vitro genotoxic potential.
Area of Science:
- Toxicology
- Genetics
- Environmental Health
Background:
- 1,3-Butadiene is a known industrial chemical with potential genotoxic and carcinogenic effects.
- Understanding its genotoxicity across species is crucial for human risk assessment.
- Genotoxic metabolites, 3,4-epoxybutene (EB) and 1,2:3,4-diepoxybutane (DEB), are key to butadiene's toxicity.
Purpose of the Study:
- To evaluate the genotoxicity of 1,3-butadiene and its metabolites (EB, DEB) in various in vitro and in vivo systems.
- To determine if animal cell findings can predict human toxicity from 1,3-butadiene exposure.
- To compare the susceptibility of rats and mice to 1,3-butadiene's genotoxic effects.
Main Methods:
- Sister chromatid exchange (SCE) and micronucleus induction assays in mouse and rat bone marrow.
- Unscheduled DNA synthesis (UDS) assays in rat and mouse hepatocytes (in vivo and in vitro).
- Salmonella typhimurium (Ames) gene mutation tests with different metabolic activation systems (S9) and in vitro SCE in human lymphocytes.
Main Results:
- 1,3-Butadiene induced genotoxicity (SCE, micronucleus) in mouse bone marrow but not rat bone marrow, mirroring carcinogenicity data.
- No unscheduled DNA synthesis (UDS) was observed for 1,3-butadiene in vivo or for EB and DEB in vitro.
- Weak mutagenicity (Ames test) was observed only in Salmonella strain TA1535 under specific conditions; in vitro SCE in human lymphocytes was negative.
Conclusions:
- 1,3-Butadiene exhibits significant in vivo genotoxicity, with species-specific differences (mice > rats).
- The metabolites EB and DEB show limited genotoxic potential in vitro, particularly regarding DNA synthesis.
- Overall, 1,3-butadiene acts as an in vivo genotoxin but a weak in vitro genotoxin, with implications for extrapolating animal data to humans.