The use of benchmark dose uncertainty measurements for robust comparative potency analyses

التفاصيل البيبلوغرافية
العنوان: The use of benchmark dose uncertainty measurements for robust comparative potency analyses
المؤلفون: George E. Johnson, Ryan P Wheeldon, Stephen D. Dertinger, Jeffrey C. Bemis, Steven M. Bryce
بيانات النشر: Wiley, 2021.
سنة النشر: 2021
مصطلحات موضوعية: Epidemiology, In vitro genotoxicity, Health, Toxicology and Mutagenesis, 010501 environmental sciences, 01 natural sciences, Models, Biological, Risk Assessment, Histones, 03 medical and health sciences, Statistics, Potency, Animals, Humans, Point estimation, Lymphocytes, Relative potency, Genetics (clinical), Volume concentration, 030304 developmental biology, 0105 earth and related environmental sciences, Mathematics, 0303 health sciences, Dose-Response Relationship, Drug, Mutagenicity Tests, Uncertainty, Confidence interval, Benchmarking, Gene Expression Regulation, Mutagenesis, Benchmark (computing), Tumor Suppressor Protein p53, Stepwise approach, DNA Damage, Mutagens
الوصف: The Benchmark Dose (BMD) method is the favored approach for quantitative dose-response analysis where uncertainty measurements are delineated between the upper (BMDU) and lower (BMDL) confidence bounds, or confidence intervals (CIs). Little has been published on the accurate interpretation of uncertainty measurements for potency comparative analyses between different test conditions. We highlight this by revisiting a previously published comparative in vitro genotoxicity dataset for human lymphoblastoid TK6 cells that were exposed to each of 10 clastogens in the presence and absence (+/-) of low concentration (0.25%) S9, and scored for p53, γH2AX and Relative Nuclei Count (RNC) responses at two timepoints (Tian et al. 2020). The researchers utilized BMD point estimates in potency comparative analysis between S9 treatment conditions. Here we highlight a shortcoming that the use of BMD point estimates can mischaracterize potency differences between systems. We reanalyzed the dose responses by BMD modelling using PROAST v69.1. We used the resulting BMDL and BMDU metrics to calculate "S9 potency ratio confidence intervals" that compare the relative potency of compounds +/- S9 as more statistically robust metrics for comparative potency measurements compared to BMD point estimate ratios. We performed unsupervised hierarchical clustering that identified four S9-dependent groupings: high and low-level potentiation, no effect, and diminution. This work demonstrates the importance of using BMD uncertainty measurements in potency comparative analyses between test conditions. Irrespective of the source of the data, we propose a stepwise approach when performing BMD modelling in comparative potency analyses between test conditions.
اللغة: English
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6a14db34f3bba340cd6a846d8353b7c5
https://cronfa.swan.ac.uk/Record/cronfa56076/Download/56076__19181__eb84a9f54d9d43ce863726d100a51223.pdf
Rights: OPEN
رقم الانضمام: edsair.doi.dedup.....6a14db34f3bba340cd6a846d8353b7c5
قاعدة البيانات: OpenAIRE