10 research outputs found
In silico toxicology protocols
The present publication surveys several applications of in silico (i.e., computational) toxicology approaches across different industries and institutions. It highlights the need to develop standardized protocols when conducting toxicity-related predictions. This contribution articulates the information needed for protocols to support in silico predictions for major toxicological endpoints of concern (e.g., genetic toxicity, carcinogenicity, acute toxicity, reproductive toxicity, developmental toxicity) across several industries and regulatory bodies. Such novel in silico toxicology (IST) protocols, when fully developed and implemented, will ensure in silico toxicological assessments are performed and evaluated in a consistent, reproducible, and well-documented manner across industries and regulatory bodies to support wider uptake and acceptance of the approaches. The development of IST protocols is an initiative developed through a collaboration among an international consortium to reflect the state-of-the-art in in silico toxicology for hazard identification and characterization. A general outline for describing the development of such protocols is included and it is based on in silico predictions and/or available experimental data for a defined series of relevant toxicological effects or mechanisms. The publication presents a novel approach for determining the reliability of in silico predictions alongside experimental data. In addition, we discuss how to determine the level of confidence in the assessment based on the relevance and reliability of the information
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Mechanisms of Hepatoprotection in a Murine Model of Bile Acid-Induced Intrahepatic Cholestasis
There are many causes of cholestasis, which results when the flow of bile acids is slowed or stopped. Bile acids are hydrophobic molecules synthesized from cholesterol in the liver, and when present in excess, are cytotoxic to cell membranes. Treatment options for cholestasis are limited, and if left untreated or inadequately treated, many patients will require a liver transplant; thus, underscoring the importance of successfully managing this disease. Activation of nuclear receptors in animal models has been shown to be hepatoprotective during bile acid-induced cholestasis; however, the mechanisms underlying the hepatoprotective effects are poorly understood. Therefore, the over-arching goal of this project is to glean an improved comprehension of the mechanisms of hepatoprotection during bile acid-induced cholestasis. All of the studies involve administration of CAR activators phenobarbital (PB), oltipraz (OPZ), 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene [TCPOBOP (TC)] or corn oil (CO) to C57BL/6 wild type (WT), or WT and CAR knockout (CAR-/-) mice prior to induction of intrahepatic cholestasis using the secondary bile acid lithocholic acid (LCA). Efflux transport proteins such as Mrps 3 and 4 are known to be up-regulated during cholestasis, and this was the first topic of exploration. Unexpectedly, the expression of efflux transporters was not consistently up-regulated in protected mice. However, a decrease in total liver bile acid concentrations was observed. These changes in hepatic bile acids indicated that bile acid biosynthesis may be relevant to hepatoprotection. Indeed decreases in total and individual bile acids correlated with hepatoprotection, and Cyp8b1 expression was also increased which could be suggestive of a shift in the bile acid biosynthesis pathway towards the formation of less toxic bile acid species. CAR may also have a role in cell death via apoptosis by altering Bcl-2 protein expression. Although apoptosis was decreased in hepatoprotected mice, an increase in the expression of Mcl-1 and Bcl-xL was not observed, suggesting hepatoprotection is not a direct result of CAR-induced Mcl-1 expression. These findings add significantly to the body of knowledge surrounding cholestatic liver disease and suggest that studies aimed toward manipulation of nuclear receptors are worthy of further exploration
Updating the waste prevention programme : preparing the foundations for updating the waste prevention programme based on an analysis and evaluation of the implementation status ; final report
The waste prevention program (WPP) from 2013 must be evaluated every 6 years and updated if necessary. The review and evaluation of the implementation of the WPP took place within the scope of the project. Based on the analysis results for the implementation of the WPP at federal, state and municipal level and an assessment of existing prevention potentials, concrete proposals for a possible further development and updating of the program on prioritized waste streams and corresponding priority prevention approaches were developed. In addition, structural adjustment and change needs of the WPP were worked out and further research was shown
Constitutive Androstane Receptor-Mediated Changes in Bile Acid Composition Contributes to Hepatoprotection from Lithocholic Acid-Induced Liver Injury in MiceS⃞
Pharmacological activation of the constitutive androstane receptor (CAR)
protects the liver during cholestasis. The current study evaluates how
activation of CAR influences genes involved in bile acid biosynthesis as a
mechanism of hepatoprotection during bile acid-induced liver injury. CAR
activators phenobarbital (PB) and 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene
(TCPOBOP) or corn oil (CO) were administered to C57BL/6 wild-type (WT) and CAR
knockout (CAR-null) mice before and during induction of intrahepatic
cholestasis using the secondary bile acid, lithocholic acid (LCA). In
LCA-treated WT and all the CAR-null groups (excluding controls), histology
revealed severe multifocal necrosis. This pathology was absent in WT mice
pretreated with PB and TCPOBOP, indicating CAR-dependent hepatoprotection.
Decreases in total hepatic bile acids and hepatic monohydroxy, dihydroxy, and
trihydroxy bile acids in PB- and TCPOBOP-pretreated WT mice correlated with
hepatoprotection. In comparison, concentrations of monohydroxylated and
dihydroxylated bile acids were increased in all the treated CAR-null mice
compared with CO controls. Along with several other enzymes (Cyp7b1, Cyp27a1,
Cyp39a1), Cyp8b1 expression was increased in hepatoprotected mice, which could
be suggestive of a shift in the bile acid biosynthesis pathway toward the
formation of less toxic bile acids. In CAR-null mice, these changes in gene
expression were not different among treatment groups. These results suggest
CAR mediates a shift in bile acid biosynthesis toward the formation of less
toxic bile acids, as well as a decrease in hepatic bile acid concentrations.
We propose that these combined CAR-mediated effects may contribute to the
hepatoprotection observed during LCA-induced liver injury
Fortschreibung Abfallvermeidungsprogramm : Erarbeitung der Grundlagen für die Fortschreibung des Abfallvermeidungsprogramms auf Basis einer Analyse und Bewertung des Umsetzungsstandes ; Abschlussbericht
2013 wurde das Abfallvermeidungsprogramm des Bundes verabschiedet. Mit dem Programm sollten Abfallmengen reduziert werden. Das Programm wurde einer kritischen Bewertung unterzogen und wird nun im Jahr 2020 fortgeschrieben. Dafür wurden in einer UBA-Studie prioritäre Abfallströme und Konzepte erarbeitet und Maßnahmenvorschläge entwickelt, um die Abfallvermeidung zukünftig konkreter auszugestalten
Extending (Q)SARs to incorporate proprietary knowledge for regulatory purposes: A case study using aromatic amine mutagenicity
Statistical-based and expert rule-based models built using public domain mutagenicity knowledge and data are routinely used for computational (Q)SAR assessments of pharmaceutical impurities in line with the approach recommended in the ICH M7 guideline. Knowledge from proprietary corporate mutagenicity databases could be used to increase the predictive performance for selected chemical classes as well as expand the applicability domain of these (Q)SAR models. This paper outlines a mechanism for sharing knowledge without the release of proprietary data. Primary aromatic amine mutagenicity was selected as a case study because this chemical class is often encountered in pharmaceutical impurity analysis and mutagenicity of aromatic amines is currently difficult to predict. As part of this analysis, a series of aromatic amine substructures were defined and the number of mutagenic and non-mutagenic examples for each chemical substructure calculated across a series of public and proprietary mutagenicity databases. This information was pooled across all sources to identify structural classes that activate or deactivate aromatic amine mutagenicity. This structure activity knowledge, in combination with newly released primary aromatic amine data, was incorporated into Leadscope's expert rule-based and statistical-based (Q)SAR models where increased predictive performance was demonstrated.JRC.I.5-Systems Toxicolog
In silico approaches in organ toxicity hazard assessment: Current status and future needs in predicting liver toxicity
Hepatotoxicity is one of the most frequently observed adverse effects resulting from exposure to a xenobiotic. For example, in pharmaceutical research and development it is one of the major reasons for drug withdrawals, clinical failures, and discontinuation of drug candidates. The development of faster and cheaper methods to assess hepatotoxicity that are both more sustainable and more informative is critically needed. The biological mechanisms and processes underpinning hepatotoxicity are summarized and experimental approaches to support the prediction of hepatotoxicity are described, including toxicokinetic considerations. The paper describes the increasingly important role of in silico approaches and highlights challenges to the adoption of these methods including the lack of a commonly agreed upon protocol for performing such an assessment and the need for in silico solutions that take dose into consideration. A proposed framework for the integration of in silico and experimental information is provided along with a case study describing how computational methods have been used to successfully respond to a regulatory question concerning non-genotoxic impurities in chemically synthesized pharmaceuticals
Table1_Developing a pragmatic consensus procedure supporting the ICH S1B(R1) weight of evidence carcinogenicity assessment.pdf
The ICH S1B carcinogenicity global testing guideline has been recently revised with a novel addendum that describes a comprehensive integrated Weight of Evidence (WoE) approach to determine the need for a 2-year rat carcinogenicity study. In the present work, experts from different organizations have joined efforts to standardize as much as possible a procedural framework for the integration of evidence associated with the different ICH S1B(R1) WoE criteria. The framework uses a pragmatic consensus procedure for carcinogenicity hazard assessment to facilitate transparent, consistent, and documented decision-making and it discusses best-practices both for the organization of studies and presentation of data in a format suitable for regulatory review. First, it is acknowledged that the six WoE factors described in the addendum form an integrated network of evidence within a holistic assessment framework that is used synergistically to analyze and explain safety signals. Second, the proposed standardized procedure builds upon different considerations related to the primary sources of evidence, mechanistic analysis, alternative methodologies and novel investigative approaches, metabolites, and reliability of the data and other acquired information. Each of the six WoE factors is described highlighting how they can contribute evidence for the overall WoE assessment. A suggested reporting format to summarize the cross-integration of evidence from the different WoE factors is also presented. This work also notes that even if a 2-year rat study is ultimately required, creating a WoE assessment is valuable in understanding the specific factors and levels of human carcinogenic risk better than have been identified previously with the 2-year rat bioassay alone.</p