No abstract

No abstract

Derisking xenobiotic-induced nongenotoxic carcinogenesis (NGC) represents a significant challenge during the safety assessment of chemicals and therapeutic drugs. The identification of robust mechanism-based NGC biomarkers has the potential to enhance cancer hazard identification. We previously demonstrated Constitutive Androstane Receptor (CAR) and WNT signaling-dependent up-regulation of the pluripotency associated Dlk1-Dio3 imprinted gene cluster noncoding RNAs (ncRNAs) in the liver of mice treated with tumor-promoting doses of phenobarbital (PB). Here, we have compared phenotypic, transcriptional ,and proteomic data from wild-type, CAR/PXR double knock-out and CAR/PXR double humanized mice treated with either PB or chlordane, and show that hepatic Dlk1-Dio3 locus long ncRNAs are upregulated in a CAR/PXR-dependent manner by two structurally distinct CAR activators. We further explored the specificity of Dlk1-Dio3 locus ncRNAs as hepatic NGC biomarkers in mice treated with additional compounds working through distinct NGC modes of action. We propose that up-regulation of Dlk1-Dio3 cluster ncRNAs can serve as an early biomarker for CAR activator-induced nongenotoxic hepatocarcinogenesis and thus may contribute to mechanism-based assessments of carcinogenicity risk for chemicals and novel therapeutics.

Limits for the carry-over of product residues should be based on toxicological evaluation such as described in the "Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities". The toxicological evaluation should be performed also for locally administered drugs to ensure patient safety. Currently, there is no guidance on setting PDE for ocular drug substances in particular. The purpose of this investigation was to identify and describe a method for calculating a PDE value for topical ocular drugs (PDE). As an alternative method, extrapolation of a PDE for systemically administered drugs to a PDE is presented. These methods may be applied in cross-contamination risk assessments for manufacturing of topical ocular drugs. Similarly, the methods apply to systemically administered drugs, if their production precedes manufacturing of a topical ocular drug. We have examined pharmacokinetic (PK) properties of topical ocular drugs and compared them to the PK parameters of systemically administered drugs. Furthermore, we examined possible adverse effects of the carry-over in topical ocular drugs at therapeutic doses.

No abstract