Microbial mutagenicity studies with (Z)-1,3-dichloropropene

Watson, William P.; Brooks, T.M.; Huckle, Keith R.; Hutson, D. H.; Lang, Krystyna L.; Smith, Robert P.; Wright, A. N.

doi:10.1016/0009-2797(87)90016-0

Cited by 22 publications

(15 citation statements)

References 10 publications

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“…1,3-D-containing pesticides appeared to be direct-acting mutagens in the TA100 and TA1535 strains of Salmonella typhimurium (15), but this was due in TA100 to polar impurities (16) subsequently identified as cis-and trans-1,3-D-epoxides formed by autoxidation in equal amounts (17). The 1,3-D-epoxide impurities must be removed prior to studies of intrinsic genotoxicity and metabolic activation and other toxicological investigations.…”

Section: Introductionmentioning

confidence: 99%

1,3-Dichloropropene Epoxides: Intermediates in Bioactivation of the Promutagen 1,3-Dichloropropene

Schneider

Quistad

Casida

1998

Chem. Res. Toxicol.

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1,3-Dichloropropene (1,3-D), a major soil fumigant nematicide, is genotoxic in many types of assays, leading to its classification as possibly carcinogenic in humans. This study tests in three steps the hypothesis that 1,3-D is a promutagen activated by epoxidation and further reaction of the 1,3-D-epoxides. Stereospecific epoxidation of 1,3-D (examined as the cis/trans mixture and as individual isomers) to the corresponding cis- and trans-1,3-D-epoxides is demonstrated here for the first time, both in vitro in a mouse liver microsome-NADPH system and in vivo in the liver of ip-treated mice, using GC/MS for product identification and quantitation. The cis epoxide is observed in higher yield than the trans epoxide, both in vitro and in vivo, and the cis isomer also reacts slower than the trans isomer with GSH alone or catalyzed by GSH S-transferase. cis- and trans-1,3-D-Epoxides are stable in acetone or chloroform but degrade completely in Me2SO exclusively to 2-chloroacrolein (30 min at 40 degrees C). Epoxide decomposition is slower in pH 7.4 phosphate buffer (t1/2 = 116 and 64 min for cis and trans, respectively, at 41 degrees C) with a >99% yield of 3-chloro-2-hydroxypropanal (and its dimer) and <0.5% formation of 2-chloroacrolein (for which the t1/2 is 248 min at 41 degrees C). Mutagenicity assays in Salmonella typhimurium TA100 (standard plate incorporation) establish high potencies of 37, 17, and 150 revertants/nmol for cis- and trans-1, 3-D-epoxides and 2-chloroacrolein, respectively. The mutagenicity of the epoxides is due either to their direct action or to a degradation product formed at physiological pH, i.e., 3-chloro-2-hydroxypropanal or its dehydrochlorination products. The candidate mutagens methylglyoxal and glycidaldehyde are not detected as breakdown products of 3-chloro-2-hydroxypropanal at pH 7.4 and also have low mutagenic activity in TA100. It is therefore proposed that the penultimate and ultimate mutagens of 1,3-D metabolism are the corresponding epoxides and their direct hydrolysis product 3-chloro-2-hydroxypropanal, respectively.

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Section: Introductionmentioning

confidence: 99%

1,3-Dichloropropene Epoxides: Intermediates in Bioactivation of the Promutagen 1,3-Dichloropropene

Schneider

Quistad

Casida

1998

Chem. Res. Toxicol.

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“…Polar impurities of the preparations were too complex to be totally characterized, but two of them were tentatively identified as epichlorophydrin and 1 , 3-d ich loro-2-propanol . Watson et al,25 confirmed that impurities from commerical DCP (removed by silicic acid chromatography) were responsible for mutagenicity seen in TA100. These impurities, identified as cis-and trans-2-chloro-3-(chloromethyl) oxiranes, were the result of autoxidation of the compound.…”

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confidence: 80%

Toxicology and Hazard Assessment of 1,3-Dichloropropene (Telone® II)

Albrecht

1987

Archives of Environmental Health: An International Journal

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“…Significantly, addition of cytosolic fractions that contain glutathione-S-transferase, and physiological levels of glutathione to in vitro mutagenicity assays, have been found to eliminate mutagenic activity of purified or oxidized samples of 1,3-dichloropropene (Watson et al, 1987;B. Gollapudi, unpublished data).…”

Section: Short-term Assaysmentioning

confidence: 98%

“…A number of early in vitro assays reporting positive responses for 1,3dichloropropene in bacteria (De Lorenzo et al, 1977;Eder et al, 1982;Neudecker et al, 1977;Stolzenberg and Hine, 1980) were confounded by the presence of mutagenic impurities and/or stabilizing agent (e.g., epichlorohydrin) or by the generation of mutagenic oxidation products during gas chromatographic purification procedures (Talcott and King, 1984;Watson et al, 1987). A number of early in vitro assays reporting positive responses for 1,3dichloropropene in bacteria (De Lorenzo et al, 1977;Eder et al, 1982;Neudecker et al, 1977;Stolzenberg and Hine, 1980) were confounded by the presence of mutagenic impurities and/or stabilizing agent (e.g., epichlorohydrin) or by the generation of mutagenic oxidation products during gas chromatographic purification procedures (Talcott and King, 1984;Watson et al, 1987).…”

Section: Short-term Assaysmentioning

confidence: 99%

“…Affected tissues often represented portal-of-entry tissues, for example gastric mucosa for ingested and nasal mucosa for inhaled 1,3-dichloropropene, consistent with the irritant nature of this chemical. As reviewed by Watson et al (1987) and in the IPCS (1993) review, this metabolism provides for practical thresholds in the dose response of toxicity, and even mutagenicity, of 1,3-dichloropropene in test organisms. In most bioassays, tumorigenic responses, when present, have Chapter | 106 1,3-Dichloropropene Table 106.…”

Section: Dose Responsementioning

confidence: 99%

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