Physiologically-Based Kinetics and Mechanistic Models to Assess Exposure to Chemicals

In our modern society we are exposed to a myriad of chemical substances. Before these substances can be brought onto the market for use and consumption, their safety – when used as intended – needs to be confirmed in a risk assessment. Typically, a risk assessment comprises a toxicological hazard assessment, the quantification of a dose-response relationship, an exposure assessment and a risk characterisation under the assessed conditions. Traditionally, a toxicological hazard assessment is performed in vivo in laboratory animals, and more recently, in targeted in vitro testing. However, due to calls for replacement, reduction and refinement of animal testing alternative methods such as in silico models are increasingly being used. Also, increasing emphasis is being placed on understanding mechanisms and pathways of toxicity as well as quantifying exposure which leads to an adverse effect in individuals. Physiologically-based kinetic and mechanistic models allow for a mathematical description of causal relationships between an exposure scenario and a toxicological outcome in a biological system. While much research has been focussed on investigating mechanisms of hepatotoxicity, little is known about adverse effects induced in the kidney and only limited computational models exist to investigate nephrotoxicity. However, the kidney is a major target for toxicity by pharmaceuticals and environmental pollutants. Accumulation is known to play an important role in certain nephrotoxicity pathways. Therefore, physiologically-based kinetic and mechanistic models are considered to offer valuable insights into mechanisms of nephrotoxicity. This thesis addresses the growing attention given to exposure-based and toxicokinetics-driven toxicity which has resulted in increasing recent application of PBK modelling. The overall aim of this thesis was to propose novel ways to use publicly available data for the quantitative assessment of adverse effects induced in the kidney following chemical exposure. The first part of this thesis examines the suitability of publicly available PBK models for the prediction of urine-level concentrations in the general population following oral doses of various chemicals. Human biomonitoring (HBM) data were used for validation of simulation results and a mixture risk assessment to illustrate how predictions may be used in a risk assessment context. The second part of this thesis shows the development of a mechanistic kidney model embedded in a full-body PBK model parameterised for aspirin (ASA) and salicylic acid (SA). The research presented herein demonstrates the generation of a novel kidney model which is set up for a young and healthy individual; this was amended to simulate kinetics of elderly individuals and tested for three exposure scenarios. Key challenges in this endeavour revolve around limited data available in the public literature and uncertainties related to scaling in vitro data to an in vivo setting

The normative evolution of corporate governance in the UK : an empirical analysis (1995-2014)

Purpose This paper aims to analyse normative corporate governance evolution in the UK between 1995 and 2014 against the benchmark of Organisation for Economic Co-Operation and Development (OECD) regulatory principles. Design/methodology/approach Methodologically, the authors conduct an empirical, longitudinal data set analysis of the formative years of UK normative corporate governance development between 1995 and 2014. We provide a qualitative discussion of the empirical evidence that links the type of UK regulatory corporate governance development to financial market growth thereby adopting a mixed approach based on quantitative and qualitative research methods. Findings The authors find that compared to the OECD model of corporate governance, the UK model is less rigid following a more self-regulatory approach based upon a “comply or explain” paradigm. Thus it is scored below corporate governance systems that follow a compulsory implementation model. However, even with such “low” tilt towards formal shareholder primacy norms, the UK has the best performing financial market. As a quasi-empirical study, the authors suggest that there are several historical and economic reasons for this, which together with a robust rule of law in the UK contribute to this performance – and the law especially the type or tilt is less relevant. Originality/value This is the first of its kind empirical, longitudinal data set analysis with qualitative elements that links empirical evidence to regulatory developments in the wider context of UK corporate governance evolution

Caspofungin for treatment of invasive aspergillosis in Germany: results of a pre-planned subanalysis of an international registry

<p>Abstract</p> <p>Background</p> <p>This study is a pre-planned country-specific subanalysis of results in Germany from a multinational multicenter registry to prospectively assess real-world experience with caspofungin administered for treatment of proven or probable invasive aspergillosis (IA).</p> <p>Methods</p> <p>Data from patients treated with caspofungin for a single episode of IA were collected. Effectiveness was determined by the local investigator as favorable (complete or partial response) or unfavorable (stable disease, failure or death) at the end of caspofungin therapy. Descriptive statistics with binomial exact confidence intervals were employed.</p> <p>Results</p> <p>Forty-two consecutive patients were identified in three German centers. Three patients (7%) had proven IA and 39/42 (93%) had probable IA (modified European Organization for Research and Treatment of Cancer/Mycosis Study Group (EORTC/MSG) criteria). Forty-one patients had pulmonary IA and one had tracheal IA. Caspofungin monotherapy was received by 36/42 patients (86%); of these, 26/36 (72%) received salvage therapy. A favorable response was observed in 29/42 patients (69%; 95% CI 53 to 82%); of these, 21/29 (72%) had a complete and 8/29 (28%) a partial response. Favorable response rate was 69% in patients with monotherapy (95% CI 52% to 84%; 25/36 patients), and 67% in patients receiving combination therapy (95% CI 22% to 96%; 4/6 patients). Favorable response rate in patients with first line therapy was 64% (95% CI 31% to 89%; 7/11 patients), and 73% in patients with second line therapy (95% CI 54% to 88%; 20/30 patients). No adverse events were reported. In total, 35/42 patients (83%; 95% CI 69 to 93%) survived seven days after completion of caspofungin therapy.</p> <p>Conclusions</p> <p>These real-life findings in Germany are consistent with the international findings from this registry and with findings from randomized studies.</p

Physiologically based kinetic (PBK) modelling and human biomonitoring data for mixture risk assessment

Human biomonitoring (HBM) data can provide insight into co-exposure patterns resulting from exposure to multiple chemicals from various sources and over time. Therefore, such data are particularly valuable for assessing potential risks from combined exposure to multiple chemicals. One way to interpret HBM data is establishing safe levels in blood or urine, called Biomonitoring Equivalents (BE) or HBM health based guidance values (HBM-HBGV). These can be derived by converting established external reference values, such as tolerable daily intake (TDI) values. HBM-HBGV or BE values are so far agreed only for a very limited number of chemicals. These values can be established using physiologically based kinetic (PBK) modelling, usually requiring substance specific models and the collection of many input parameters which are often not available or difficult to find in the literature. The aim of this study was to investigate the suitability and limitations of generic PBK models in deriving BE values for several compounds with a view to facilitating the use of HBM data in the assessment of chemical mixtures at a screening level. The focus was on testing the methodology with two generic models, the IndusChemFate tool and High-Throughput Toxicokinetics package, for two different classes of compounds, phenols and phthalates. HBM data on Danish children and on Norwegian mothers and children were used to evaluate the quality of the predictions and to illustrate, by means of a case study, the overall approach of applying PBK models to chemical classes with HBM data in the context of chemical mixture risk assessment. Application of PBK models provides a better understanding and interpretation of HBM data. However, the study shows that establishing safety threshold levels in urine is a difficult and complex task. The approach might be more straightforward for more persistent chemicals that are analysed as parent compounds in blood but high uncertainties have to be considered around simulated metabolite concentrations in urine. Refining the models may reduce these uncertainties and improve predictions. Based on the experience gained with this study, the performance of the models for other chemicals could be investigated, to improve the accuracy of the simulations

Towards a qAOP Framework for Predictive Toxicology - Linking Data to Decisions

The adverse outcome pathway (AOP) is a conceptual construct that facilitates organisation and interpretation of mechanistic data representing multiple biological levels and deriving from a range of methodological approaches including in silico, in vitro and in vivo assays. AOPs are playing an increasingly important role in the chemical safety assessment paradigm and quantification of AOPs is an important step towards a more reliable prediction of chemically induced adverse effects. Modelling methodologies require the identification, extraction and use of reliable data and information to support the inclusion of quantitative considerations in AOP development. An extensive and growing range of digital resources are available to support the modelling of quantitative AOPs, providing a wide range of information, but also requiring guidance for their practical application. A framework for qAOP development is proposed based on feedback from a group of experts and three qAOP case studies. The proposed framework provides a harmonised approach for both regulators and scientists working in this area

Differences in genotype and virulence among four multidrug-resistant <i>Streptococcus pneumoniae</i> isolates belonging to the PMEN1 clone

We report on the comparative genomics and characterization of the virulence phenotypes of four &lt;i&gt;S. pneumoniae&lt;/i&gt; strains that belong to the multidrug resistant clone PMEN1 (Spain&lt;sup&gt;23F&lt;/sup&gt; ST81). Strains SV35-T23 and SV36-T3 were recovered in 1996 from the nasopharynx of patients at an AIDS hospice in New York. Strain SV36-T3 expressed capsule type 3 which is unusual for this clone and represents the product of an in vivo capsular switch event. A third PMEN1 isolate - PN4595-T23 - was recovered in 1996 from the nasopharynx of a child attending day care in Portugal, and a fourth strain - ATCC700669 - was originally isolated from a patient with pneumococcal disease in Spain in 1984. We compared the genomes among four PMEN1 strains and 47 previously sequenced pneumococcal isolates for gene possession differences and allelic variations within core genes. In contrast to the 47 strains - representing a variety of clonal types - the four PMEN1 strains grouped closely together, demonstrating high genomic conservation within this lineage relative to the rest of the species. In the four PMEN1 strains allelic and gene possession differences were clustered into 18 genomic regions including the capsule, the blp bacteriocins, erythromycin resistance, the MM1-2008 prophage and multiple cell wall anchored proteins. In spite of their genomic similarity, the high resolution chinchilla model was able to detect variations in virulence properties of the PMEN1 strains highlighting how small genic or allelic variation can lead to significant changes in pathogenicity and making this set of strains ideal for the identification of novel virulence determinant

A critical review of adverse effects to the kidney: mechanisms, data sources and in silico tools to assist prediction

Introduction: The kidney is a major target for toxicity elicited by pharmaceuticals and environmental pollutants. Standard testing which often does not investigate underlying mechanisms has proven not to be an adequate hazard assessment approach. As such, there is an opportunity for the application of computational approaches that utilise multi-scale data based on the Adverse Outcome Pathway (AOP) paradigm, coupled with an understanding of the chemistry underpinning the molecular initiating event (MIE) to provide a deep understanding of how structural fragments of molecules relate to specific mechanisms of nephrotoxicity. The aim of this investigation was to review the current scientific landscape related to computational methods, including mechanistic data, AOPs, publicly available knowledge bases and current in silico models, for the assessment of pharmaceuticals and other chemicals with regard to their potential to elicit nephrotoxicity. A list of over 250 nephrotoxicants enriched with, where possible, mechanistic and AOP-derived understanding was compiled. Expert opinion: Whilst little mechanistic evidence has been translated into AOPs, this review identified a number of data sources of in vitro, in vivo and human data that may assist in the development of in silico models which in turn may shed light on the inter-relationships between nephrotoxicity mechanisms

Exploring the evidence base for national and regional policy interventions to combat resistance

The effectiveness of existing policies to control antimicrobial resistance is not yet fully understood. A strengthened evidence base is needed to inform effective policy interventions across countries with different income levels and the human health and animal sectors. We examine three policy domains—responsible use, surveillance, and infection prevention and control—and consider which will be the most effective at national and regional levels. Many complexities exist in the implementation of such policies across sectors and in varying political and regulatory environments. Therefore, we make recommendations for policy action, calling for comprehensive policy assessments, using standardised frameworks, of cost-effectiveness and generalisability. Such assessments are especially important in low-income and middle-income countries, and in the animal and environmental sectors. We also advocate a One Health approach that will enable the development of sensitive policies, accommodating the needs of each sector involved, and addressing concerns of specific countries and regions