A workflow to practically apply true dose considerations to in vitro testing for next generation risk assessment.

With the move away from safety testing assessment based on data generated in experimental animals the concept of Next Generation Risk Assessment (NGRA) has arisen which instead uses data from in silico and in vitro models. A key uncertainty in risk assessment is the actual dose of test chemical at the target site, and therefore surrogate dose metrics, such as nominal concentration in test media are used to describe in vitro effect (or no-effect) doses. The reliability and accuracy of the risk assessment therefore depends largely on our ability to understand and characterise the relationship between the dose metrics used and the actual biologically effective dose at the target site. The objective of this publication is to use 40 case study chemicals to illustrate how in vitro dose considerations can be applied to characterise the "true dose" and build confidence in the understanding of the biologically effective dose in in vitro test systems for the determination e.g. points of departure (PoDs) for NGRA. We propose a workflow that can be applied to assess whether the nominal test concentration can be considered a conservative dose metric for use in NGRA. The workflow examines the implications of volatility, stability, hydrophobicity, binding to plastic and serum, solubility, and the potential use of in silico models for some of these parameters. For the majority of the case study chemicals we found that the use of nominal concentrations in risk assessment would result in conservative decision making. However, for serval chemicals a potential for underestimation of the risk in humans in vivo based on in vitro nominal effect concentrations was identified, and approaches for refinement by characterisation of the actual effect concentration are proposed.

Implementing cone-beam computed tomography-guided online adaptive radiotherapy in cervical cancer.

Background and purpose: Adaptive radiotherapy (ART) in locally advanced cervical cancer (LACC) has shown promising outcomes. This study investigated the feasibility of cone-beam computed tomography (CBCT)-guided online ART (oART) for the treatment of LACC. Material and methods: The quality of the automated radiotherapy treatment plans and artificial intelligence (AI)-driven contour delineation for LACC on a novel CBCT-guided oART system were assessed. Dosimetric analysis of 200 simulated oART sessions were compared with standard treatment. Feasibility of oART was assessed from the delivery of 132 oART fractions for the first five clinical LACC patients. The simulated and live oART sessions compared a fixed planning target volume (PTV) margin of 1.5 cm around the uterus-cervix clinical target volume (CTV) with an internal target volume-based approach. Workflow timing measurements were recorded. Results: The automatically-generated 12-field intensity-modulated radiotherapy plans were comparable to manually generated plans. The AI-driven organ-at-risk (OAR) contouring was acceptable requiring, on average, 12.3 min to edit, with the bowel performing least well and rated as unacceptable in 16 % of cases. The treated patients demonstrated a mean PTV D98% (+/-SD) of 96.7 (+/- 0.2)% for the adapted plans and 94.9 (+/- 3.7)% for the non-adapted scheduled plans (p<10-5). The D2cc (+/-SD) for the bowel, bladder and rectum were reduced by 0.07 (+/- 0.03)Gy, 0.04 (+/-0.05)Gy and 0.04 (+/-0.03)Gy per fraction respectively with the adapted plan (p <10-5). In the live.setting, the mean oART session (+/-SD) from CBCT acquisition to beam-on was 29 +/- 5 (range 21-44) minutes. Conclusion: CBCT-guided oART was shown to be feasible with dosimetric benefits for patients with LACC. Further work to analyse potential reductions in PTV margins is ongoing.