Combining in vitro embryotoxicity data with physiologically based kinetic (PBK) modelling to define in vivo dose-response curves for developmental toxicity of phenol in rat and human. | LitMetric
Division of Toxicology, Wageningen University, Tuinlaan 5, 6703 HE, Wageningen, The Netherlands.
Published: September 2013
AI Article Synopsis
Article Abstract
In vitro assays are often used for the hazard characterisation of compounds, but their application for quantitative risk assessment purposes is limited. This is because in vitro assays cannot provide a complete in vivo dose-response curve from which a point of departure (PoD) for risk assessment can be derived, like the no observed adverse effect level (NOAEL) or the 95 % lower confidence limit of the benchmark dose (BMDL). To overcome this constraint, the present study combined in vitro data with a physiologically based kinetic (PBK) model applying reverse dosimetry. To this end, embryotoxicity of phenol was evaluated in vitro using the embryonic stem cell test (EST), revealing a concentration-dependent inhibition of differentiation into beating cardiomyocytes. In addition, a PBK model was developed on the basis of in vitro and in silico data and data available from the literature only. After evaluating the PBK model performance, effective concentrations (ECx) obtained with the EST served as an input for in vivo plasma concentrations in the PBK model. Applying PBK-based reverse dosimetry provided in vivo external effective dose levels (EDx) from which an in vivo dose-response curve and a PoD for risk assessment were derived. The predicted PoD lies within the variation of the NOAELs obtained from in vivo developmental toxicity data from the literature. In conclusion, the present study showed that it was possible to accurately predict a PoD for the risk assessment of phenol using in vitro toxicity data combined with reverse PBK modelling.
Background: As the primary organ of metabolism and detoxification, the liver may contribute to the pathogenesis of lung cancer. We aimed to illuminate the intricate link between liver function biomarkers and lung cancer risk, as well as delineate the role of smoking behavior within this association.
Methods: We investigated the associations of seven liver function biomarkers levels (alkaline phosphatase [ALP], alanine transaminase [ALT], total bilirubin [TBIL], albumin [ALB], gamma-glutamyltransferase [GGT], aspartate transaminase [AST], and total protein [TP]) with lung cancer risk across the UK Biobank (N = 337 499) through restricted cubic splines and Cox proportional hazards models.
Department of Gastrointestinal and Minimally Invasive Surgery, Shaoxing Second Hospital, Shaoxing, Zhejiang, China; Department of Clinical Medicine, Shaoxing University School of Medicine, Zhejiang, China. Electronic address:
Stress radionuclide myocardial perfusion imaging (MPI) has been well-established as a useful modality for assessing the status of the coronary circulation in post-coronary artery bypass graft (CABG) patients. CABG by itself escalates progression of atherosclerosis or thrombosis in bypassed native coronary arteries. In most cases MPI will be employed in post-CABG patients who are experiencing symptoms.
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