Microbiological risk assessments generally focus on estimating adverse human health risks from exposures to human pathogenic microbes. The assessment of potential human health risks posed by ...pathogens that have acquired resistance to antimicrobial drugs is a new application of risk assessment that is closely related to microbiological risk assessment. Antimicrobial resistance risk assessment is a risk analytical process that focuses on resistance determinants as hazardous agents that might lead to drug-resistant microbial infections in humans exposed to bacteria carrying the determinants. Antimicrobial-resistant infections could occur directly from actively invading or opportunistic pathogens or indirectly from the transfer of resistance genes to other bacteria. Here, we discuss risk assessment models that might be employed to estimate risks from drug-resistant bacteria in the animal food pathway and the types of models and data that may be used for microbiological risk assessments or antimicrobial resistance risk assessments.
Our recent syntheses of chryseno4,5-bcdthiophene together with its potential sulfone metabolite, chryseno4,5-bcdthiophene-4,4-dioxide, have made these compounds available for genotoxicity testing. ...Such toxicity testing is of interest as this thiophene is an isoster of the established carcinogen benzoapyrene and is one of the thiaarenes which are potential environmental contaminants found in fossil fuels. Although the thiophene was less mutagenic than benzoapyrene in Salmonella strains TA98 and TA100 after S9 activation, it exhibited in vivo chromosomal aberration activity equal to that of benzoapyrene in the bone-marrow cells of mice. A reduced activity with Salmonella as well as in the bone-marrow cell assay for the sulfone does not support its role as the key active metabolic intermediate for the genotoxicity of the thiophene. Our molecular orbital calculations would be consistent with the concept of activation through a diol-epoxide mechanism and offers an explanation for the reduced genotoxicity of the sulfone via this mechanism. These genotoxicity studies support the concern that sulfur isosters of established carcinogenic polycyclic aromatic hydrocarbons could themselves be toxic.
The Ames procedure with Salmonella typhimurium strain TA100 was used to follow the detoxication by rat liver fractions of two series of aliphatic epoxides. The epoxides employed were 3-chloro-, ...3,3-dichloro- and 3,3,3-trichloropropylene oxides and also p-methoxyphenyl-, phenyl- and p-nitrophenylglycidyl ethers. In our procedure with preincubation of the epoxides with rat liver fractions prior to the Ames tests, there was more detoxication of both systems by glutathione conjugation (non-enzymatic and transferase promoted) than by the hydrolase pathways. Non-enzymatic reaction with glutathione was more pronounced for the chloro series than for the glycidyl ethers. An HPLC system was developed which was capable of quantitative measurements of the phenylglycidyl ethers together with their diol and glutathione conjugate products. A comparison of the HPLC and Ames test results indicates that the glutathione transferase reported to be present in Salmonella could be playing a role in detoxication by the Ames test. Diols were measured more readily by HPLC than by use of the Ames test in the microsomal fraction and were detected in the cytosol with the glycidyl ethers while they were not by the Ames procedure. However, all three epoxides were converted to a greater extent to their glutathione conjugates than to their diols. Thus, while literature references question the availability of the glutathione detoxication system for epoxides produced by membrane-bound enzymes, such detoxication would be of primary importance where direct-acting environmental epoxides come into contact with the cytosolic enzymes prior to possible reaction with bionucleophiles.
The mutagenicity in Salmonella and in vivo sister chromatid exchange in the bone-marrow cells of mice was determined for 1,4-, 1,3-, 2,4-, and 3,4-dimethylphenanthrene (DMPh) with the objective to ...study the relative importance of substitution at the 1 and 4 positions of this series of methylated phenanthrenes. For both tests, 1,4- DMPh was decidedly more genotoxic than the remaining regioisomers. While the well recognized role of steric crowding in the bay region is a factor in this enhanced genotoxicity, equally important is substitution at the 1 position with its potential to inhibit detoxication through 9,10-diol formation.
We report the observation of the decay $B^{-} \rightarrow D^{(*)+}_{s} K^{-} \ell^{-} \bar{\nu}_{\ell}$ based on $342 \mathrm {\,fb}^{-1}}$ of data collected at the $\Y4S$ resonance with the BABAR ...detector at the PEP-II $e^{+}e^{-}$ storage rings at SLAC. A simultaneous fit to three $D^{+}_{s}$ decay chains is performed to extract the signal yield from measurements of the squared missing mass in the B meson decay. We observe the decay $B^{-} \rightarrow D^{(*)+}_{s} K^{-} \ell^{-} \bar{\nu}_{\ell}$ with a significance greater than five standard deviations (including systematic uncertainties) and measure its branching fraction to be $\BR(B^{-} \rightarrow D^{(*)+}_{s} K^{-} \ell^{-} \bar{\nu}_{\ell}) = 6.13^{+1.04}_{-1.03}(\mathrm{stat.})\pm0.43(\mathrm{syst.}) \pm 0.51(\BR(D_{s}))\times10^{-4}$, where the last error reflects the limited knowledge of the $D_{s}$ branching fractions.
Benzidine and its 3,3'-diamino, 3,3'-dimethyl, 3,3'-dimethoxy, 3,3'-difluoro, 3,3'-dichloro, 3,3'-dibromo, 3,3'-dicarbomethoxy and 3,3'-dinitro derivatives together with 2-nitrobenzidine and ...3-nitrobenzidine were compared for their in vitro and in vivo genotoxicity. Relative mutagenicity was established with Salmonella strains TA98, TA98/1,8-DNP6 and TA100 with and without S9 activation. All the derivatives in the presence of S9 were more mutagenic than benzidine with 3,3'-dinitro- and 3-nitro-benzidine having the greatest mutagenicity. Mutagenicity in all 3 strains with S9 activation could be correlated to electron-withdrawing ability of substituent groups, as measured by the basicity of the amines. This correlation was explained on the basis that electron-withdrawing groups could favor the stability of the mutagenic intermediate N-hydroxylamine and also enhance the reactivity of the ultimate mutagenic species, the nitrenium ion. Mutagenicity was also correlated to the energy of the lowest unoccupied molecular orbitals (ELUMO). Hydrophobicity was found to have very limited effect on the relative mutagenicity of our benzidine derivatives. The in vivo endpoint was chromosomal aberrations in the bone-marrow cells of mice following intraperitoneal administration of benzidine and its derivatives. In contrast to the in vitro results, while all the amines were genotoxic in vivo, only the 3-nitro derivative had a significant increase in toxicity over benzidine.
The (R)- and (S)-optical isomers of 9 epoxides, benzyloxymethyloxirane, epichlorohydrin, glycidol, glycidyl 3-nitrobenzenesulfonate, glycidyl 4-nitrobenzoate, glycidyl tosylate, styrene oxide, ...glycidyl 1-naphthyl ether and glycidyl 4-nitrophenyl ether, have been compared for their in vivo and in vitro genotoxicity. The in vitro short-term test employed was the Ames mutagenicity assay with Salmonella strain TA100. The in vivo tests were chromosomal aberrations (CA) as well as sister-chromatid exchange (SCE) in bone-marrow cells of mice following intraperitoneal administration of these epoxides. Differences in mutagenicity between isomers were established with TA100 for all the compounds. While 13 of the isomers were genotoxic compared to a negative control by CA measurements, only in the case of glycidyl 4-nitrobenzoate could a significant difference be found between isomers by this test. However, with SCE evaluations, differences were detected between the (R)- and (S)-isomers for all the pairs of compounds with the exception of those for benzyloxymethyloxirane and glycidyl 4-nitrophenyl ether. At least in part, differences in the patterns of genotoxicity among compounds can be related to their differences in reaction pathways.
4-Amino-4'-substituted biphenyls and 4-aminostilbenes substituted in the 3' or 4' position were studied for their in vitro and in vivo genotoxicity. The in vitro mutagenicity of the biphenyls with ...and without S9 activation was established with Salmonella strains TA98 and TA100 and that of the stilbenes with the same strains plus TA98/1,8-DNP6. The in vivo genotoxicity assay with both series of compounds was for chromosomal aberrations in the bone-marrow cells of mice following intraperitoneal administration of the chemicals. Hammett values of substituents, partition coefficients and frontier orbital energies (ELUMO and EHOMO) of the compounds were used for correlations with mutagenicity. The Salmonella mutagenicity in TA98 and TA98/1,8-DNP6 with S9 was correlated to Hammett sigma + values for the 4-aminostilbene substituents, showing a strong trend of increasing mutagenicity with an increase in the electron-withdrawing capability of the substituent. Hydrophobicity of the stilbenes, however, had little effect on their relative mutagenicity. The 4-aminobiphenyls showed a correlation between their mutagenicity and Hammett sigma + values of their 4'-substituents in stain TA98 with S9, although the trend was not as strong as for the stilbenes. But unlike the stilbenes, TA98 mutagenicity of the biphenyls could also be correlated to hydrophobicity, and structure-activity correlations for the biphenyls was substantially improved when both sigma + and hydrophobicity data were included. For strain TA100 with S9, little correlation was found between mutagenicity of the stilbenes and any of the parameters. However, a limited correlation did exist between the mutagenicity of the biphenyls and their hydrophobicity. There was also limited correlations of the mutagenicity for the stilbenes in TA98 and TA98/1,8-DNP6 with S9 to ELUMO or EHOMO. The in vivo genotoxicity results for the biphenyls and stilbenes could not be correlated to electronic effects as for the in vitro results, nor could they be explained by hydrophobicity. However, it is interesting to note that 3'-substituted 4-aminostilbenes were all substantially more genotoxic in vivo than their corresponding 4'-substituted counterparts. The most genotoxic compound in vivo in either series was 4-aminostilbene which would not have been predicted from the in vitro results.
We report a direct measurement of $D^0-overline{D}^0$ mixing parameters through a time-dependent amplitude analysis of the Dalitz plots of $D^0 \rightarrow K_S^0 \pi^+ \pi^-$ and, for the first time, ...$D^0 \rightarrow K_S^0 K^+ K^-$ decays. The low-momentum pion $\pi_s^+$ in the decay $D^{*+} \rightarrow D^0 \pi_s^+$ identifies the flavor of the neutral $D$ meson at its production. Using 468.5 fb$^{-1}$ of $e^+e^-$ colliding-beam data recorded near $\sqrt s = 10.6$~GeV by the BABAR detector at the PEP-II asymmetric-energy collider at SLAC, we measure the mixing parameters $x= 1.6 \pm 2.3 ({\rm stat.}) \pm 1.2 ({\rm syst.}) \pm 0.8 ({\rm model}) \times10^{-3}$, and $y= 5.7 \pm 2.0 ({\rm stat.}) \pm 1.3 ({\rm syst.}) \pm 0.7 ({\rm model}) \times 10^{-3}$. These results disfavor the no-mixing hypothesis with a significance of 1.9 standard deviations, and provide the best measurement to date of $x$.
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