Metabolic Activation of Haloalkanes and Tests in vitro for Mutagenicity

Uehleke, H.; Werner, Therese; Greim, H.; Kramer, M. Gabriela

doi:10.3109/00498257709038707

Cited by 6 publications

(10 citation statements)

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“…The results have been generally negative. For instance, two groups reported that chloroform failed to induce mutations in Salmonella typhimurium (21,22), and chloroform was also negative in a sex-linked recessive lethal test conducted in Drosophila melanogaster (23). Most recently, chloroform was selected as one of several prototype chemicals to be evaluated in a comprehensive battery of short term tests for carcinogenicity.…”

Section: Discussionmentioning

confidence: 99%

Mechanistic Considerations for Carcinogenic Risk Estimation: Chloroform

Reitz¹,

Fox²,

Quast³

1982

Environmental Health Perspectives

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Chloroform has been reported to induce cancer in rodents after chronic administration of high doses by gavage. However, the interpretation of these findings is hampered by a lack of knowledge concerning the relative roles of genetic and nongenetic mechanisms in these bioassays. The present studies were carried out in male B6C3F1 mice in order to investigate the potential of chloroform to induce genetic damage and/or organ toxicity at the sites where tumors have been observed in the various bioassays. These studies revealed that carcinogenic doses of chloroform produced severe necrosis at the sites where tumors later developed. This was demonstrated by light microscopy as well as by determination of the cellular regeneration index following administration of 3H-thymidine. Noncarcinogenic doses of chloroform failed to induce these responses. In contrast, studies of DNA alkylation and DNA repair in vivo failed to give any indication that chloroform had produced the type of genetic alterations associated with known genotoxic chemicals. These data suggest that the-primary mechanism of chloroform-induced carcinogenesis is nongenetic in nature. If the same mechanism predominates in man, there should be little to no carcinogenic risk associated with exposure to noncytotoxic levels of chloroform.

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Section: Discussionmentioning

confidence: 99%

Mechanistic Considerations for Carcinogenic Risk Estimation: Chloroform

Reitz¹,

Fox²,

Quast³

1982

Environmental Health Perspectives

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“…Therefore, the toxicity and carcinogenicity of CHC13 may be related to its metabolism to phosgene. Several studies demonstrate that reactive CHC13 metabolites covalently bind to protein and lipid [Sipes et al, 1977;Docks and Krishna, 1976;Uehleke and Werner, 1975;Uehleke et al, 1977;Ilett et al, 19731.…”

Section: Covalent Binding To Macromoleculesmentioning

confidence: 99%

A review of the mutagenicity of chloroform

Rosenthal

1987

Environ and Mol Mutagen

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Although chloroform (CHCl3) is metabolized in vivo and in vitro to a substance that covalently interacts with protein and lipid, its potential for binding to DNA is low. In addition, most of the assays for genotoxicity are negative. However, many of the genotoxicity results are inconclusive because of inadequacies in the experimental protocols. The types of genotoxicity tests this report is based on include bacterial, yeast, host-mediated, Drosophila sex-linked recessive lethal, mammalian cell mutagenicity, sperm head abnormality, cytogenetic, and DNA damage. On the basis of presently available information, no definitive conclusion on the mutagenic potential of CHCl3 can be reached.

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“…Several reports indicate that carbon tetrachloride is not mutagenic in S. typhimurium tester strains using either the pourplate or preincubation method Uehleke et al, 1977;Zeiger et al, 1988]; chloroform also is negative in S. typhimurium and E. coli tester strains using these testing protocols [Simmon et al, 1977;Uehleke et al, 1977;Gocke et al, 1981;Kirkland et al, 1981;Van Abbe et al, 1982]. We previously performed a literature review which indicated that some poorly water-soluble, volatile compounds such as 1-bromopropane (boiling point, 71°C) and 1-bromobutane (boiling point 102°C) give negative bacterial mutagenicity responses when using the pour-plate or preincubation methods, but have produced positive response when a gas exposure method is employed [Araki et.…”

Section: Introductionmentioning

confidence: 99%

Mutagenicity of carbon tetrachloride and chloroform in Salmonella typhimurium TA98, TA100, TA1535, and TA1537, and Escherichia coli WP2uvrA/pKM101 and WP2/pKM101, using a gas exposure method

Araki

Kamigaito

Sasaki

et al. 2004

Environ and Mol Mutagen

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The volatile solvents carbon tetrachloride and chloroform are carcinogens that are often reported as nonmutagenic in bacterial mutagenicity assays. In this study, we evaluated the mutagenicity of these compounds in Salmonella typhimurium TA98, TA100, TA1535, and TA1537, and Escherichia coli WP2uvrA/pKM101 and WP2/pKM101, with and without S9 mix, using a gas exposure method. Tests were also conducted with a glutathione-supplemented S9 mix. Carbon tetrachloride was mutagenic in TA98 without S9 mix, and in WP2/pKM101 and WP2uvrA/pKM101 with and without S9 mix; carbon tetrachloride was not mutagenic in TA100, TA1535 or TA1537. Chloroform was mutagenic in WP2/pKM101, but only in the presence of glutathione-supplemented S9 mix. Chloroform was not mutagenic in TA98, TA100, TA1535, TA1537, or WP2uvrA/pKM101 with or without S9 mix, and was not mutagenic in TA98, TA100, TA1535, TA1537, or WP2uvrA/pKM101 in the presence of glutathione-supplemented S9 mix. The data indicate that carbon tetrachloride and chloroform are bacterial mutagens when adequate exposure conditions are employed and suggest that a genotoxic mode of action could contribute to the carcinogenicity of these compounds.

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Metabolic Activation of Haloalkanes and Tests in vitro for Mutagenicity

Cited by 6 publications

References 0 publications

Mechanistic Considerations for Carcinogenic Risk Estimation: Chloroform

Mechanistic Considerations for Carcinogenic Risk Estimation: Chloroform

A review of the mutagenicity of chloroform

Mutagenicity of carbon tetrachloride and chloroform in Salmonella typhimurium TA98, TA100, TA1535, and TA1537, and Escherichia coli WP2uvrA/pKM101 and WP2/pKM101, using a gas exposure method

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