Search

The mycotoxins zearalenone and alternariol may contaminate food and feed raising toxicological concerns due to their estrogenicity. Inter-species differences in their toxicokinetics and toxicodynamics may occur depending on evolution of taxa-specific traits. As a proof of principle, this manuscript investigates the comparative toxicodynamics of zearalenone, its metabolites (alpha-zearalenol and beta-zearalenol), and alternariol with regards to estrogenicity in humans and rainbow trout. An in silico structural approach based on docking simulations, pharmacophore modeling and molecular dynamics was applied and computational results were analyzed in comparison with available experimental data. The differences of estrogenicity among species of zearalenone and its metabolites have been structurally explained. Also, the low estrogenicity of alternariol in trout has been characterized here for the first time. This approach can provide a powerful tool for the characterization of interspecies differences in mycotoxin toxicity for a range of protein targets and relevant compounds for the food- and feed-safety area., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

We investigated dose-fractionated polymyxin B (PB) on acute kidney injury (AKI). PB at 12 mg of drug/kg of body weight per day (once, twice, and thrice daily) was administered in rats over 72 h. The thrice-daily group demonstrated the highest KIM-1 increase ( P  = 0.018) versus that of the controls ( P  = 0.99) and histopathological damage ( P  = 0.013). A three-compartment model best described the data (bias, 0.129 mg/liter; imprecision, 0.729 mg 2 /liter 2 ; R 2 , 0.652,). Area under the concentration-time curve at 24 h (AUC 24 ) values were similar ( P  = 0.87). The thrice-daily dosing scheme resulted in the most PB-associated AKI in a rat model., (Copyright © 2020 American Society for Microbiology.)

Colistin is administered as its inactive prodrug colistimethate (CMS). Selection of an individualized CMS dose for each patient is difficult due to its narrow therapeutic window, especially in patients with chronic kidney disease (CKD). Our aim was to analyze CMS use in patients with CKD. Secondary objectives were to assess the safety and efficacy of CMS in this special population. In this prospective observational cohort study of CMS-treated CKD patients, CKD was defined as the presence of a glomerular filtration rate (GFR) < 60 mL/min/m2 for more than 3 months. The administered doses of CMS were compared with those recently published in the literature. Worsened CKD at the end of treatment (EOT) was evaluated with the RIFLE (Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease) criteria. Colistin plasma concentrations (Css) were measured using high-performance liquid chromatography. Fifty-nine patients were included. Thirty-six (61.2%) were male. The median age was 76 (45–95) years and baseline GFR was 36.6 ± 13.6. The daily mean CMS dosage used was compared with recently recommended doses (3.36 vs. 6.07; p < 0.001). Mean Css was 0.9 (0.2–2.9) mg/L, and Css was <2 mg/L in 50 patients (83.3%). Clinical cure was achieved in 43 (72.9%) patients. Worsened renal function at EOT was present in 20 (33.9%) patients and was reversible in 10 (52.6%). The CMS dosages used in this cohort were almost half those currently recommended. The mean achieved Css were under the recommended target of 2 mg/dL. Despite this, clinical cure rate was high. In this patient cohort, the incidence of nephrotoxicity was similar to those found in other recent studies performed in the general population and was reversible in 52.6%. These results suggest that CMS is safe and effective in patients with CKD and may encourage physicians to adjust dosage regimens to recent recommendations in order to optimize CMS treatments. [ABSTRACT FROM AUTHOR]

Background/aim: Oxaliplatin-induced chronic neuropathy is a prominent factor for dose reduction and not completing all cycles of chemotherapy for patients with colorectal cancer (CRC). The aim of the study was to investigate the pharmacokinetics and toxicodynamics of oxaliplatin-induced chronic neuropathy in CRC rats to ensure effective management., Materials and Methods: A rat model of CRC was developed using 1,2-Dimethylhydrazine and dextran sulfate. Oxaliplatin (L-OHP) was administered intravenously to CRC rats every week. The pharmacokinetic profiles and tumor distribution of L-OHP and chronic neuropathies were investigated for over four weeks., Results: The mean values of the area under the concentration-time curve for L-OHP showed a dose-dependent increase. Chronic neuropathy occurred from Day 14 in the 8 mg/kg group and Day 19 in the 3 and 5 mg/kg groups., Conclusion: These results provide preliminary information for the development of a pharmacokinetic and toxicodynamic model of L-OHP for CRC therapy cycles., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

The purpose of this paper is to describe the use of toxicokinetic (TK) and toxicodynamic (TD) data in setting acceptable daily exposure (ADE) values and occupational exposure limits (OELs). Use of TK data can provide a more robust exposure limit based on a rigorous evaluation of systemic internal dose. Bioavailability data assist in extrapolating across different routes of exposure to be protective for route-based differences of exposure. Bioaccumulation data enable extrapolation to chronic exposures when the point of departure (PoD) is from a short-term critical study. Applied in the context of chemical-specific adjustment factors (CSAFs), TK data partially replace traditional default adjustment factors for interspecies extrapolation (extrapolation from studies conducted in animals to humans) and intraspecies variability (to account for human population variability). Default adjustments of 10-fold each for interspecies and intraspecies extrapolation are recommended in several guidelines, although some organization recommend other values. Such default factors may overestimate variability for many APIs, while not being sufficiently protective for variability with other APIs. For this reason, the use of chemical specific TK and TD data are preferred. Making full use of existing TK and TD data reduces underlying uncertainties, increases transparency, and ensures that resulting ADEs reflect the best available science. [ABSTRACT FROM AUTHOR]

In this paper, we review recent publications regarding the toxicokinetics and -dynamics of the flame retardant Hexabromocyclododecane (HBCD). HBCD has recently been listed as a persistent organic pollutant, which therefore influenced the legislation concerning its manufacturing and formulation. However, under specific circumstances it may still be used until 2024. Early toxicity studies have only focussed on HBCD itself, which is a mixture of different isomers with different physical and toxicological characteristics. Here we take a more differentiated look at the three diastereomers α-, β- and γ-HBCD. We also address the different enantiomers to give an overview of the toxicity of HBCD to identify present gaps in our knowledge about this chemical, especially with respect to its possible formulation until 2024., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

A critical challenge for environmental chemical risk assessment is the characterization and reduction of uncertainties introduced when extrapolating inferences from one species to another. The purpose of this article is to explore the challenges, opportunities, and research needs surrounding the issue of how genomics data and computational and systems level approaches can be applied to inform differences in response to environmental chemical exposure across species. We propose that the data, tools, and evolutionary framework of comparative genomics be adapted to inform interspecies differences in chemical mechanisms of action. We compare and contrast existing approaches, from disciplines as varied as evolutionary biology, systems biology, mathematics, and computer science, that can be used, modified, and combined in new ways to discover and characterize interspecies differences in chemical mechanism of action which, in turn, can be explored for application to risk assessment. We consider how genetic, protein, pathway, and network information can be interrogated from an evolutionary biology perspective to effectively characterize variations in biological processes of toxicological relevance among organisms. We conclude that comparative genomics approaches show promise for characterizing interspecies differences in mechanisms of action, and further, for improving our understanding of the uncertainties inherent in extrapolating inferences across species in both ecological and human health risk assessment. To achieve long-term relevance and consistent use in environmental chemical risk assessment, improved bioinformatics tools, computational methods robust to data gaps, and quantitative approaches for conducting extrapolations across species are critically needed. Specific areas ripe for research to address these needs are recommended., (Copyright © 2011 Elsevier Inc. All rights reserved.)