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In pesticide risk assessment, regulatory acceptable concentrations for surface water bodies (RACsw,ch) are used that are derived from standard studies with continuous exposure of organisms to a test compound for days or months. These RACsw,ch are compared with the maximum tested concentration of more realistic exposure scenarios. However, the actual exposure duration could be notably shorter (e.g., hours) than the standard study, which intentionally leads to an overly conservative Tier 1 risk assessment. This discrepancy can be addressed in a risk assessment using the time-weighted average concentration (TWAc). In Europe, the applicability of TWAc for a particular risk assessment is evaluated using a complex decision scheme, which has been controversial; thus we propose an alternative approach: We used TWAc-check (which is based on the idea that the TWAc concept is just a model for aquatic risk assessment) to test whether the use of a TWAc is appropriate for such assessment. The TWAc-check method works by using predicted-measured diagrams to test how well the TWAc model predicts experimental data from peak exposure experiments. Overestimated effects are accepted because the conservatism of the TWAc model is prioritized over the goodness of fit. We illustrate the applicability of TWAc-check by applying it to various data sets for different species and substances. We demonstrate that the applicability is case dependent. Specifically, TWAc-check correctly identifies that the use of TWAc is not appropriate for early onset of effects or delayed effects. The proposed concept shows that the time window is a decisive factor as to whether or not the model is acceptable and that this concept can be used as a potential refinement option prior to the use of toxicokinetic-toxicodynamic models. Environ Toxicol Chem 2022;41:1778-1787. © 2022 Bayer AG. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

In order to evaluate the ability of the cell-penetrating α-helical amphipathic model peptide KLALKLALKALKAALKLA-NH2 (MAP) to deliver peptide nucleic acids (PNAs) into mammalian cells, MAP was covalently linked to the 12-mer PNA 5′-GGAGCAGGAAAG-3′ directed against the mRNA of the nociceptin/orphanin FQ receptor. The cellular uptake of both the naked PNA and its MAP-conjugate was studied by means of capillary electrophoresis combined with laser-induced fluorescence detection, confocal laser scanning microscopy and fluorescence-activated cell sorting. Incubation with the fluorescein-labelled PNA–peptide conjugate led to three- and eightfold higher intracellular concentrations in neonatal rat cardiomyocytes and CHO cells, respectively, than found after exposure of the cells to the naked PNA. Correspondingly, pretreatment of spontaneously-beating neonatal rat cardiomyocytes with the PNA–peptide conjugate and the naked PNA slowed down the positive chronotropic effect elicited by the neuropeptide nociceptin by 10- and twofold, respectively. The main reasons for the higher bioavailability of the PNA–peptide conjugate were found to be a more rapid cellular uptake in combination with a lowered re-export and resistance against influences of serum.