No abstract

Two hydroxypyridinone-containing actinide decorporation agents, 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO), are being developed for the treatment of internal actinide contamination by chelation therapy. Dose-response efficacy profiles in mice were established for the removal of intravenously injected 238Pu and 241Am after parenteral and oral treatment with these chelators. In both cases, presumed efficacious doses promoted substantially greater actinide elimination rates than the currently approved agent, diethylenetriamine-pentaacetic acid, considering two different interspecies scaling methods for the conversion of human doses to equivalent rodent dose levels. In addition, genotoxicity of both ligands was assessed using the Salmonella/Escherichia coli/microsome plate incorporation test and the Chinese hamster ovary cell chromosome aberration assay, showing that neither ligand is genotoxic, in the presence and absence of metabolic activation. Finally, maximum tolerated dose studies were performed in rats for seven consecutive daily oral administrations with the chelators, confirming the safety of the presumed efficacious doses for 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO). The results of these studies add to the growing body of evidence that both decorporation agents have remarkable decorporation efficacy properties and promising safety toxicology profiles. These results are necessary components of the regulatory approval process and will help determine the optimal human dosing regimens for the treatment of internal radionuclide contamination.

The potential health benefits of green tea continue to attract public and scientific interests and are attributed in part to polyphenolic catechin constituents. Polyphenon E (Poly E) is a decaffeinated green tea catechin mixture containing about 50% epigallocatechin gallate and 30% other catechins. We evaluated the toxicity and genotoxicity of Poly E by using two in vitro assays: bacterial mutagenesis in a Salmonella typhimurium-E. coli assay and the L5178Y mouse lymphoma cell thymidine kinase (Tk) gene mutation assay. In addition, we used two in vivo genotoxicity assays: the mouse micronucleus assay and the Big Blue cII transgenic mouse mutation assay. Repeat-dose toxicity evaluations were performed in mice in parallel with the Big Blue transgenic mutation assays. No significant increases in the revertant colonies were found in the bacterial mutagenesis assay, but a significant increase in the mutant frequency (MF) at the Tk locus was observed in the mouse lymphoma test system. We observed toxicity in mice when Poly E was administered at doses of 2,000 mg/kg/day. Lower doses produced no significant increases in micronucleated erythrocytes in the bone marrow of Swiss-Webster mice and no significant increases in cII transgene MF in the liver, lung, or spleen compared with controls. These results indicate that Poly E, although toxic at high doses (2,000 mg/kg/day), poses minimal genotoxic concern. In addition, these studies highlight the importance of using both in vitro and in vivo systems in genetic toxicity screening of pharmaceuticals before they are administered to humans.

No abstract

The in vitro genotoxic activity of mainstream cigarette smoke condensate (CSC) from cigarettes which heat but do not burn tobacco was compared to that of CSC from cigarettes which burn tobacco. CSCs from five cigarettes were compared. Three of the cigarettes [the Kentucky reference research cigarette (1R4F), a commercially available ultra-low tar brand (ULT) and a commercially available ultra-low tar menthol brand (ULT-menthol]) burn tobacco while two of the cigarettes [a regular (TEST) and a menthol (TEST-menthol]) heat tobacco. CSC from all cigarettes were collected by identical standard techniques, which involved collecting mainstream smoke particulate matter on Cambridge filter pads under FTC smoking conditions. The pads were extracted with DMSO, and the CSCs obtained [10 mg total particulate matter (TPM)/ml DMSO] were evaluated at identical concentrations in an in vitro genetic toxicology test battery. CSCs from 1R4F, ULT, and ULT-menthol cigarettes were mutagenic in Ames bacterial strains TA98, TA100, TA1537, and TA1538 in the presence of metabolic activation (S9 from Aroclor-induced rat liver) but negative in strain TA1535. In the absence of metabolic activation, 1R4F, ULT, and ULT-menthol CSCs were not mutagenic except for a weak response in strain TA1537 for the 1R4F and ULT CSCs. TEST and TEST-menthol CSCs were nonmutagenic in all five bacterial strains, both with and without metabolic activation. CSCs from 1R4F, ULT, and ULT-menthol cigarettes were positive in the CHO-chromosomal aberration assay and in the CHO--sister chromatid exchange assay both with and without metabolic activation while TEST and TEST-menthol CSCs were negative in both assays, either with or without metabolic activation. CSCs from 1R4F, ULT, and ULT-menthol cigarettes were weakly positive in inducing DNA repair in cultured rat hepatocytes while TEST and TEST-menthol CSCs were negative in this assay. All five CSCs were nonmutagenic in the CHO-HGPRT assay both with and without metabolic activation. CSCs from the 1R4F, ULT, and ULT-menthol cigarettes were cytotoxic in the CHO-HGPRT assay, both with and without metabolic activation, while TEST and TEST-menthol CSCs were not cytotoxic under either condition. These results demonstrate that mainstream CSCs from the TEST and TEST-menthol cigarettes are neither genotoxic nor cytotoxic under conditions where CSCs from 1R4F, ULT, and ULT-menthol cigarettes are genotoxic and/or cytotoxic in a concentration-dependent manner.