Marta Morotti

Genetic safety evaluation of pesticides in different short-term tests

Cyanazine, cyhexatin, dicamba and DNOC are pesticides commonly and broadly used in agriculture pest control. However, there is little information on their toxicity and mutagenicity in human cells and in whole animals. Therefore, UDS assay and SCE assay in human peripheral lymphocytes, and chromosome aberration analysis in bone marrow of rats have been used to assess the DNA-damaging activity of the above pesticides. Cyanazine proved non-genotoxic in all the test systems. Cyhexatin showed only weakly positive results for SCE induction in human lymphocytes, providing no concern for genotoxicological hazard. While dicamba did not show clastogenic effects in rodents, DNOC gave significant dose-related increases of structural chromosome aberrations in rat bone marrow cells. Female animals showed increased sensitivity to the toxic effects by DNOC at the highest dose. The results provide further information on the intrinsic genotoxic activity of the tested pesticides, which may contribute to the toxicological assessment of the risk associated with human exposure.

Mechanism of genotoxicity and electron density distribution by NMR of 5-nitro-3-thiophenecarboxamides, a novel group of direct-acting mutagens in Salmonella typhimurium.

The mutagenic activity of 23 5-nitro-3-thiophenecarboxanilides and of 5-nitro-3-thiophenecarboxamide, the prototype, (NTCAs) have been evaluated in the Ames test on Salmonella typhimurium strains TA100 ad TA98 with and without metabolic activation. Effects of different substituents (electron-donating and electron-withdrawing) were studied to evaluate structural features that affect the metabolism and the bacterial mutagenic potency. All the derivatives were direct-acting mutagens, the mutagenic potency ranging from 0.7 to 142 revertants (rev.)/nmol in TA100 and from 0.09 to 68 rev./nmol in TA98 strain. Results obtained with strains TA98NR and TA98/1,8-DNP6 indicated that the mutagenic activity was largely dependent on bacterial nitroreductase, whereas the O-acetylation step was not critical for mutagenic potency. Superoxide (O2-.) and hydroxyl (OH.) scavengers as well as other radical scavengers and enzymes inhibited NTCAs mutagenicity to different extents. In particular, O2-. seemed to be involved in NTCAs mutagenicity, showing a free radical pathway for NTCA metabolism. [1H]- and [13C]NMR data indicated that the effects of different substituents on genotoxicity are probably not exerted on the electron density distribution. The importance of factors such as extent of nitration, reduction potential, orientation of nitrosubstituent and planarity of the molecule are discussed.

Retrospective cohort analysis of liposomal amphotericin b nephrotoxicity in patients with hematological malignancies

ABSTRACT We retrospectively examined the incidence, onset, risk factors, and outcomes of renal injury during 103 treatment courses of liposomal amphotericin B (L-AMB) in 97 adult patients with hematological malignancies. All the patients were analyzed before, during, and after the administration of L-AMB, and renal injury was graded according to the RIFLE criteria (risk, injury, failure, loss of function, end-stage renal disease). Most patients (87.3%) received L-AMB at 3 mg/kg of body weight/day. Nearly two-thirds (61.7%) of the treatment courses did not meet any RIFLE category for renal injury, while 19.4% of patients were classified at risk, 13.6% met an injury classification, and 5.8% were categorized as developing renal failure. However, 15% of the patients developed renal injury within 48 h of the onset of multiorgan failure associated with sepsis, bleeding, or progressing malignancy. When these patients were analyzed as a competing risk for L-AMB-associated renal injury (RIFLE category I or above) in a multivariate Cox regression model, receipt of cyclosporine (subhazard ratio [SHR], 2.62; 95% confidence interval [CI], 1.10 to 6.27; P = 0.03), cyclosporine plus furosemide at ≥40 mg/day (SHR, 5.46; 95% CI, 1.89 to 15.74; P = 0.002), or cyclosporine plus foscarnet (SHR, 9.03; 95% CI, 3.68 to 22.14; P < 0.0001) were the only comedications significantly associated with increased rates of renal injury. The cumulative incidence of L-AMB renal injury during the first 10 days of therapy was 7% overall but only 3% in patients who were not receiving cyclosporine. Hence, the renal risk of L-AMB therapy may be lessened if patients are switched to alternative agents after 7 to 10 days or if aggressive diuresis and/or foscarnet is avoided, especially among patients receiving calcineurin inhibitors.

Murine α/β Interferons Inhibit Benzo(A)Pyrene Activation and Mutagenesis in Mice

In addition to their antiviral and immune regulatory properties, interferons (IFNs) are known to depress hepatic cytochrome P450-dependent metabolism. As many chemical mutagens and carcinogens require bioactivation by the mixed-function monooxygenase (MFO) system in order to be genotoxic, a combined genetic and biochemical approach was used to establish whether IFNs could inhibit the activation of benzo(a)pyrene (BaP) to the ultimate clastogenic metabolite(s) in vivo.