salmonella typhimurium (ta100) mutagenicity of 3‐chloro‐4‐(dichloromethyl)‐5‐hydroxy‐2(5h)‐furanone and its open‐ and closed‐ring analogs

Abstract

The mutagenicities of 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX, compound 1), 3-chloro-4-(dichloromethyl)-2(5H)-furanone (RMX, compound 6), and 2-(dichloromethyl)-3,3-dichloropropenal (TCB, compound 7) were determined in the same assay and in repetitive determinations using Salmonella typhimurium (TA 100) without microsomal fraction activation. In addition, the mutagenicity of 2-methyl-3,3-dichloropropenal (compound 8) was assayed in the same manner although not simultaneously with MX, RMX, and TCB. This study was undertaken to ascertain the role of open- and closed-ring forms of MX in the mutagenicity of MX. MX proved to be roughly 100 times more mutagenic than the open-ring analogue TCB and 10 times more mutagenic than the closed-ring analogue RMX. Compound 8 was inactive. Assay stability of the three active compounds in Vogel-Bonner medium at 38 degrees C was estimated as the chemical half-life values by following the change in UV absorbance at selected wave lengths. Half-life values were 10.7, 2.6, and 2.8 hr, respectively, for MX, RMX, and TCB. The enhanced mutagenicity of MX relative to RMX and TCB is attributed to the intrinsic mutagenicity of MX and its greater stability is judged to play only a minor role. Moreover, the greater mutagenicity of the closed-ring analogue RMX relative to the open-ring analogue TCB points to the ring form of MX as the active species even though the open form of MX is predominant under assay conditions.

Simple and α,β-unsaturated aldehydes: Correct prediction of genotoxic activity through structure-activity relationship models

“…This experience is instructive about one of the most important uses of QSAR, i.e., alerting about possible hazards, and setting priorities for experimentation. In this context, we reiterate that chemical 16 (2-methyl-3,3-dichloroacrolein), reported to be negative in Salmonella [LaLonde et al, 1991] and predicted to be positive by us [Benigni et al, 2003], should be retested. Unfortunately, chemical 16 was not available to us for testing in this current study.…”

MX, a by‐product of water chlorination, lacks in vivo genotoxicity in gpt delta mice but inhibits gap junctional intercellular communication in rat WB cells

“…In the present study, the lack of mutagenicity was linked with an absence of carcinogenicity. MX was reported to induce 2800-13000 revertants/ nmol in the Salmonella typhimurium TA100 without metabolic activation [Ishiguro et al, 1988;LaLonde et al, 1991], indicating that the compound is one of the most potent mutagens in TA100. The contribution of MX to the total mutagenicity associated with chlorine-treated tap water was estimated to be 15-57% in Finland [Kronberg and Vertiainen, 1988], 15-34% in the United States [Meier et al, 1987a], and 7-21% in Japan [Furihata et al, 1992].…”

Use of mechanism-based structure-activity relationships analysis in carcinogenic potential ranking for drinking water disinfection by-products.

“…It appears that the ultimate mutagen of MX-related compounds inside the cells may be their open-ring form, but they need to cyclize to closed-ring form outside the cells to facilitate membrane penetration. Substitution of chlorine by bromine has no appreciable effects on mutagenicity, as indicated by comparable mutagenicity among MX 4-chloromethyl generates a less potent mucochloric acid (52,54,55). On the basis of this SAR information, the cancer concern levels of the 10 MX-related DBPs in this study are summarized in Table 5, along with rationale and available genotoxicity data.…”

“…This number is not as high as would be expected from its bacterial mutagenic potency, indicating that MX may be readily detoxified in the body. The structure-mutagenicity relationships of MX and related compounds have been extensively studied using Ames Salmonella assay (49,52,53). MX is an extremely potent, direct-acting bacterial mutagen; its mutagenic activity can be substantially decreased by inclusion of S-9 mix.…”