The mutagenicity of chloroethylene oxide, chloroacetaldehyde, 2-chloroethanol and chloroacetic acid, conceivable metabolites of vinyl chloride

Rannug, Ulf; Göthe, Rolf; Wachtmeister, Carl Axel

doi:10.1016/0009-2797(76)90041-7

Cited by 161 publications

(41 citation statements)

References 16 publications

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“…However, bromoacetaldehyde is a metabolite of EDB (Hill et al, 1978) and can bind to DNA without enzymatic activation (Banerjee et al, 1979). Both 2-bromoethanol and chloroacetaldehyde are bacterial mutagens (McCann et al, 1975b;Rannug et al, 1976;Rosenkranz, 1977), but bromoacetaldehyde is not, possibly due to its extreme toxicity (Rosenkranz, 1977). Thus, the identity of the genotoxic metabolites of EDB is unclear.…”

Section: Introductionmentioning

confidence: 99%

An analysis of the mutagenicity of 1,2-dibromoethane to Escherichia coli: Influence of DNA repair activities and metabolic pathways

Foster

Wilkinson

Miller

et al. 1988

Mutation Research/DNA Repair Reports

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SummaryThe mutagenicity of 1,2-dibromoethane (EDB) to Escherichia coli was reduced by the UV lightinduced excision repair system but unaffected by the loss of a major apurinic/apyrimidinic site repair function. At high doses, 70-90% of the EDB-induced mutations were independent of SOS-mutagenic processing and approximately 50% were independent of glutathione conjugation. The SOSindependent mutations induced by EDB were unaffected by the enzymes that repair alkylationinduced DNA lesions. EDB-induced base substitutions were dominated by GC to AT and AT to GC transitions. These results suggest that EDB-induced premutagenic lesions have some, but not all, of the characteristics of simple alkyl lesions. KeywordsDibromoethane; EDB; Escherichia coil; Miscoding lesions; DNA repair 1,2-Dibromoethane (EDB or DBE; has been used as an antiknock additive in leaded gasoline, an industrial solvent, a pesticide, and a food disinfectant (NIOSH, 1977). It is one of a class of potentially hazardous compounds, the haloalkanes, that has become widely distributed in the environment . EDB is highly toxic, causing liver and kidney necrosis and reproductive abnormalities (reviews Shih and Hill, 1981;Rannug, 1980;Ter Haar, 1980). It has been repeatedly shown to be carcinogenic to rodents, resulting in tumors in a number of organs, including the forestomach, liver, spleen and thyroid (NCI, 1978). Thus environmental exposure to EDB is a potential health hazard.The mutagenicity of EDB has been demonstrated in a number of genetic systems, including bacteria, yeast and other fungi, plants, insects, mammals and human cells (reviews, Fabricant and Chalmers, 1980;Rannug, 1980). Although EDB is a direct-acting mutagen in the Salmonella/microsome assay (McCann et al., 1975a), its mutagenicity has been shown to be further enhanced by metabolic activation (Rannug, 1980). Metabolic activation of EDB to its ultimate mutagenic and carcinogenic form has been hypothesized to occur by two different (Rannug, 1980; Anders and Livesey, 1980). One, mediated by the mixed-function oxygenases of liver microsomes, would yield bromoacetaldehyde and 2-bromoethanol as potential DNA-damaging agents (Hill et al., 1978;Banerjee et al., 1979). The other pathway, conjugation with glutathione mediated by enzymes present in liver cytosol, would yield as reactive products a half-sulfur-mustard or an episulfonium ion (Rannug, 1980;van Bladeren et al., 1980). The binding of EDB to DNA in vitro has been shown to be dependent on glutathione conjugation, and an S- [2-(N 7 -guanyl)ethyl]glutathione adduct has been identified (Ozawa and Guengerich, 1983;Inskeep and Guengerich, 1984). However, bromoacetaldehyde is a metabolite of EDB (Hill et al., 1978) and can bind to DNA without enzymatic activation (Banerjee et al., 1979). Both 2-bromoethanol and chloroacetaldehyde are bacterial mutagens (McCann et al., 1975b;Rannug et al., 1976;Rosenkranz, 1977), but bromoacetaldehyde is not, possibly due to its extreme toxicity (Rosenkranz, 1977). Thus, the identity of the genotoxic metabol...

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Section: Introductionmentioning

confidence: 99%

An analysis of the mutagenicity of 1,2-dibromoethane to Escherichia coli: Influence of DNA repair activities and metabolic pathways

Foster

Wilkinson

Miller

et al. 1988

Mutation Research/DNA Repair Reports

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“…In a few cases a modification of the liquid assay according to Rannung et al (18), as described elsewhere (19), was also carried out.…”

Section: Mutagenicity and Genotoxicity Testingmentioning

confidence: 99%

Molecular mechanisms of DNA damage initiated by alpha, beta-unsaturated carbonyl compounds as criteria for genotoxicity and mutagenicity.

Eder

Hoffman

Bastian

et al. 1990

Environ Health Perspect

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,-Unsaturated carbonyl compounds are important not only from a theoretical but also a practical standpoint. These ubiquitous compounds can interact with DNA through various mechanisms. The predominant interaction is the formation of cyclic 1,N2-deoxyguanosine adducts; 7,8-cyclic guanine adducts are also found. We have synthesized and characterized the stereoisomers of adducts formed by about 20 a,ID-unsaturated carbonyl compounds. The different types of adducts and the mutagenic and genotoxic response can be explained by the molecular structures of the agents. Compounds forming saturated cyclic adducts are mutagenic in S. typhimurium strain TA100 and to a lesser extent in TA1535. Substances with a leaving group at the C-3 position form unsaturated conjugated cyclic adducts and are mutagenic only in the His D3052 frameshift strains with an intact excision repair system (no urvA mutation). Metabolic epoxidation of the double bond and other metabolic activation, e.g., activation of the nitrogroups via nitroreductases, were also found to contribute to genotoxic and mutagenic activities. Our results have further elucidated the genotoxic mechanisms of these compounds; however, additional investigations are required for a complete understanding of the genotoxic activity of this class of compounds.

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“…Weiter erwies sich Ethylenoxid mutagen für einen Adenin-abhängigen Stamm von Neurospora crassa [66,67], für Gerste [68][69][70][71][72] und Reis [73][74][75]. Bei Verwendung bakterieller Teststämme, die für Basenpaar-Substitution indikativ sind (Salmonella typhimurium TA 1535, TA 100), war Ethylenoxid ohne metabolische Aktivierung mutagen [76,77]. Die gentoxische Wirkung von Ethylenoxid auf Säugerzellen bei Exposition in vivo oder in vitro ist in der Tabelle 1 zusammengefaßt dargestellt.…”

Section: Zum Gentoxischen Und Kanzerogenen Potential Von Ethylenoxidunclassified

Ethylenoxid [MAK Value Documentation in German language, 1984]

2012

The MAK‐Collection for Occupational Health and Safety

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Veröffentlicht in der Reihe Gesundheitsschädliche Arbeitsstoffe , 10. Lieferung, Ausgabe 1984 Der Artikel enthält folgende Kapitel: Allgemeiner Wirkungscharakter ‐ Metabolismus Erfahrungen beim Menschen Tierexperimentelle Befunde Akute Toxizität Subakute und chronische Inhalationstoxizität Zum gentoxischen und kanzerogenen Potential von Ethylenoxid Zur Frage eines MAK‐Wertes

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The mutagenicity of chloroethylene oxide, chloroacetaldehyde, 2-chloroethanol and chloroacetic acid, conceivable metabolites of vinyl chloride

Cited by 161 publications

References 16 publications

An analysis of the mutagenicity of 1,2-dibromoethane to Escherichia coli: Influence of DNA repair activities and metabolic pathways

An analysis of the mutagenicity of 1,2-dibromoethane to Escherichia coli: Influence of DNA repair activities and metabolic pathways

Molecular mechanisms of DNA damage initiated by alpha, beta-unsaturated carbonyl compounds as criteria for genotoxicity and mutagenicity.

Ethylenoxid [MAK Value Documentation in German language, 1984]

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