Predicting the Acute Liver Toxicity of Aflatoxin B1 in Rats and Humans by an In Vitro–In Silico Testing Strategy

Scope: High-level exposure to aflatoxin B1 (AFB1) is known to cause acute liver damage and fatality in animals and humans. The intakes actually causing this acute toxicity have so far been estimated based on AFB1 levels in contaminated foods or biomarkers in serum. The aim of the present study is to predict the doses causing acute liver toxicity of AFB1 in rats and humans by an in vitro–in silico testing strategy. Methods and results: Physiologically based kinetic (PBK) models for AFB1 in rats and humans are developed. The models are used to translate in vitro concentration–response curves for cytotoxicity in primary rat and human hepatocytes to in vivo dose–response curves using reverse dosimetry. From these data, the dose levels at which toxicity would be expected are obtained and compared to toxic dose levels from available rat and human case studies on AFB1 toxicity. The results show that the in vitro–in silico testing strategy can predict dose levels causing acute toxicity of AFB1 in rats and human. Conclusions: Quantitative in vitro in vivo extrapolation (QIVIVE) using PBK modeling-based reverse dosimetry can predict AFB1 doses that cause acute liver toxicity in rats and human.</p

Learning in complex public systems:The case of MINUSMA’s intelligence organization

Public systems are facing increasingly complex challenges such as poverty and terrorism. In this paper, we seek to demonstrate the theoretical as well as practical value of complexity science, by investigating how key characteristics of a Complex Adaptive System (CAS) work out in practice within the intelligence organization of the ongoing nation-building mission in Mali (MINUSMA). Our main finding is that the learning properties of the CAS suffer when its structural properties are not sufficiently developed. In MINUSMA, major improvements can especially be made in (re)developing the minimum specs—in which strategic and operational demands, ideally, converge

Physiologically Based Kinetic Modeling-Facilitated Reverse Dosimetry to Predict in Vivo Red Blood Cell Acetylcholinesterase Inhibition following Exposure to Chlorpyrifos in the Caucasian and Chinese Population

Organophosphates have a long history of use as insecticides over the world. The aim of the present study was to investigate the interethnic differences in kinetics, biomarker formation, and in vivo red blood cell acetylcholinesterase inhibition of chlorpyrifos (CPF) in the Chinese and the Caucasian population. To this purpose, physiologically based kinetic models for CPF in both the Chinese and Caucasian population were developed, and used to study time-and dose-dependent interethnic variation in urinary biomarkers and to convert concentration-response curves for red blood cell acetylcholinesterase inhibition to in vivo dose-response curves in these 2 populations by reverse dosimetry. The results obtained revealed a marked interethnic difference in toxicokinetics of CPF, with lower urinary biomarker levels at similar dose levels and slower CPF bioactivation and faster chlorpyrifos-oxon detoxification in the Chinese compared with the Caucasian population, resulting in 5-to 6-fold higher CPF sensitivity of the Caucasian than the Chinese population. These differences might be related to variation in the frequency of single-nucleotide polymorphisms for the major biotransformation enzymes involved. To conclude, the interethnic variation in kinetics of CPF may affect both its biomarker-based exposure assessment and its toxicity and risk assessment and physiologically based kinetic modeling facilitates the characterization and quantification of these interethnic variations.</p

Cellular levels and molecular dynamics simulations of estragole DNA adducts point at inefficient repair resulting from limited distortion of the double-stranded DNA helix

Estragole, naturally occurring in a variety of herbs and spices, can form DNA adducts after bioactivation. Estragole DNA adduct formation and repair was studied in in vitro liver cell models, and a molecular dynamics simulation was used to investigate the conformation dependent (in)efficiency of N2-(trans-isoestragol-3′-yl)-2′-deoxyguanosine (E-3′-N2-dG) DNA adduct repair. HepG2, HepaRG cells, primary rat hepatocytes and CHO cells (including CHO wild-type and three NER-deficient mutants) were exposed to 50 μM estragole or 1′-hydroxyestragole and DNA adduct formation was quantified by LC–MS immediately following exposure and after a period of repair. Results obtained from CHO cell lines indicated that NER plays a role in repair of E-3′-N2-dG adducts, however, with limited efficiency since in the CHO wt cells 80% DNA adducts remained upon 24 h repair. Inefficiency of DNA repair was also found in HepaRG cells and primary rat hepatocytes. Changes in DNA structure resulting from E-3′-N2-dG adduct formation were investigated by molecular dynamics simulations. Results from molecular dynamics simulations revealed that conformational changes in double-stranded DNA by E-3′-N2-dG adduct formation are small, providing a possible explanation for the restrained repair, which may require larger distortions in the DNA structure. NER-mediated enzymatic repair of E-3′-N2-dG DNA adducts upon exposure to estragole will be limited, providing opportunities for accumulation of damage upon repeated daily exposure. The inability of this enzymatic repair is likely due to a limited distortion of the DNA double-stranded helix resulting in inefficient activation of nucleotide excision repair.</p

Defining in vivo dose-response curves for kidney DNA adduct formation of aristolochic acid I in rat, mouse and human by an in vitro and physiologically based kinetic modeling approach

Aristolochic acid I (AAI) is a well-known genotoxic kidney carcinogen. Metabolic conversion of AAI into the DNA-reactive aristolactam-nitrenium ion is involved in the mode of action of tumor formation. This study aims to predict in vivo AAI-DNA adduct formation in the kidney of rat, mouse and human by translating the in vitro concentration-response curves for AAI-DNA adduct formation to the in vivo situation using physiologically based kinetic (PBK) modeling-based reverse dosimetry. DNA adduct formation in kidney proximal tubular LLC-PK1 cells exposed to AAI was quantified by liquid chromatography-electrospray ionization-tandem mass spectrometry. Subsequently, the in vitro concentration-response curves were converted to predicted in vivo dose-response curves in rat, mouse and human kidney using PBK models. Results obtained revealed a dose-dependent increase in AAI-DNA adduct formation in the rat, mouse and human kidney and the predicted DNA adduct levels were generally within an order of magnitude compared with values reported in the literature. It is concluded that the combined in vitro PBK modeling approach provides a novel way to define in vivo dose-response curves for kidney DNA adduct formation in rat, mouse and human and contributes to the reduction, refinement and replacement of animal testing

Defence logistics: an important research field in need of researchers

The article of record as published may be found at http://dx.doi.org/10.1108/IJPDLM-03-2012-0079Purpose - The purpose of this paper is to provide an introduction to the special issue on defence logistics. To achieve this, an overview of the field of defence logistics is offered together with a discussion of the historical and contemporary issues that have confronted researchers and practitioners. Current research is described, and a research agenda for future work in the field is proposed. Design/methodology/approach - The paper is based upon a conceptual discussion of defence logistics as it has been studied in the past and is being studied in the present, and a reflection on the ways in which past research can usefully inform future research agendas. Findings – The paper discusses the current state of defence logistics research, and proposes a research agenda for future work based upon the anticipated characteristics of future combat operations. Research limitations/implications - A future research agenda is proposed that is informed by recent transformations in the conduct of warfare, as well as through anticipated changes in the global strategic landscape. Comparisons are made between defence logistics operations and their commercial counterparts to illustrate where there may be opportunities for adaptation based on the underlying similarities. Originality/value - This paper discusses the major threads and themes of defence logistics research as a discipline, highlights the changing landscape of conflict in the 21st century and provides a future research agenda for those working in the field

Understanding Coherence in UN Peacekeeping : A Conceptual Framework

Coherence is a core objective in most multinational interventions and seems of particular relevance to UN peacekeeping missions with their increasing complexity and multidimensionality. Yet, coherence has rarely been studied empirically. We borrow the concept of ‘fit’ from organizational theory and use it to develop a conceptual framework to study coherence in peacekeeping operations. Fit is the degree of match between what is required by the mandate, on the one hand, and an institutional set-up and the implemented practices, on the other. We identify three relevant dimensions of fit to study coherence: strategic and organizational, cultural and human and operational fit. Our empirical material focuses on the UN mission in Mali (MINUSMA) and in particular on the interplay between the intelligence components and the rest of the mission. We draw upon a large empirical dataset containing over 120 semi-structured interviews, field observations and participation in pre-deployment exercises and evaluation sessions. Our empirical analysis suggests that low level of fit across several dimensions leads to inertial and widespread frictions in the practice of peacekeeping and could potentially undermine peacekeeping effectiveness. Building on existing scholarship on micro-level approaches to peacekeeping, we hope to further the debate on organizational dynamics within peace operations