Structural Complexity and Molecular Properties of Cyclic Systems with Acyclic Branches

The degree of structural complexity of cyclic molecules with acyclic branches is quantitatively expressed by means of ·rules based on the change in the sum of the topological distances, i. e. the Wiener number, in the corresponding graphs. It is shown that these topological rules are well reflected in the properties of iso:ue1·ic alkyl-benzenes

On Characterization of Monocyclic Structures

The sum of topological distances in the molecular graph, the Wiener number, is used for a topological characterization of monocycles. Various other mathematical models based either on the adjacency matrix or on the distance matrix of a system, which were earlier used mostly for studying molecular branching, are now also applied to monocyclic structures in order to learn if they would be of use in characterizing molecular cyclicity

Development of a decision tree for mitochondrial dysfunction: Uncoupling of oxidative phosphorylation

Mitochondrial dysfunction is the result of a number of process including the uncoupling of oxidative phosphorylation. This study outlines the development of a decision tree-based profiling scheme capable of assigning chemicals to one of six confidence-based categories. The decision tree is based on a set of structural alerts and physico-chemical boundaries identified from a detailed study of the literature. The physico-chemical boundaries define a chemical relationship with both log P and pKa. The study also outlines how the decision tree can be used to profile databases through an analysis of the publically available databases in the OECD QSAR Toolbox. This analysis enabled a set of additional structural alerts to be identified that are of concern for protonophoric ability. The decision tree will be incorporated in the OECD QSAR Toolbox V4.3. The intended usage being for the grouping of chemicals into categories for chronic human health and environmental toxicological endpoints

Methods for reliability and uncertainty assessment and for applicability evaluations of classification- and regression-based QSARs

This article provides an overview of methods for reliability assessment of quantitative structure–activity relationship (QSAR) models in the context of regulatory acceptance of human health and environmental QSARs. Useful diagnostic tools and data analytical approaches are highlighted and exemplified. Particular emphasis is given to the question of how to define the applicability borders of a QSAR and how to estimate parameter and prediction uncertainty. The article ends with a discussion regarding QSAR acceptability criteria. This discussion contains a list of recommended acceptability criteria, and we give reference values for important QSAR performance statistics. Finally, we emphasize that rigorous and independent validation of QSARs is an essential step toward their regulatory acceptance and implementation. Key words: QSAR acceptability criteria, QSAR applicability domain, QSAR reliability, QSAR uncertainty estimation, QSAR validation

Workgroup Report: Review of Fish Bioaccumulation Databases Used to Identify Persistent, Bioaccumulative, Toxic Substances

Chemical management programs strive to protect human health and the environment by accurately identifying persistent, bioaccumulative, toxic substances and restricting their use in commerce. The advance of these programs is challenged by the reality that few empirical data are available for the tens of thousands of commercial substances that require evaluation. Therefore, most preliminary assessments rely on model predictions and data extrapolation. In November 2005, a workshop was held for experts from governments, industry, and academia to examine the availability and quality of in vivo fish bioconcentration and bioaccumulation data, and to propose steps to improve its prediction. The workshop focused on fish data because regulatory assessments predominantly focus on the bioconcentration of substances from water into fish, as measured using in vivo tests or predicted using computer models. In this article we review of the quantity, features, and public availability of bioconcentration, bioaccumulation, and biota–sediment accumulation data. The workshop revealed that there is significant overlap in the data contained within the various fish bioaccumulation data sources reviewed, and further, that no database contained all of the available fish bioaccumulation data. We believe that a majority of the available bioaccumulation data have been used in the development and testing of quantitative structure–activity relationships and computer models currently in use. Workshop recommendations included the publication of guidance on bioconcentration study quality, the combination of data from various sources to permit better access for modelers and assessors, and the review of chemical domains of existing models to identify areas for expansion

Read-across of 90-day rat oral repeated-dose toxicity: A case study for selected β-olefinic alcohols

There are no in vivo repeated-dose data for the vast majority of β-olefinic alcohols. However, there are robust and consistent ex vivo data suggesting many of these chemicals are metabolically transformed, especially in the liver, to reactive electrophilic toxicants which react in a mechanistically similar manner to acrolein, the reactive metabolite of 2-propen-1-ol. Hence, an evaluation was conducted to determine suitability of 2-propen-1-ol as a read-across analogue for other β-olefinic alcohols. The pivotal issue to applying read-across to the proposed category is the confirmation of the biotransformation to metabolites having the same mechanism of electrophilic reactivity, via the same metabolic pathway, with a rate of transformation sufficient to induce the same in vivo outcome. The applicability domain for this case study was limited to small (C3 to C6) primary and secondary -olefinic alcohols. Mechanistically, these -unsaturated alcohols are considered to be readily metabolised by alcohol dehydrogenase to polarised α, -unsaturated aldehydes and ketones. These metabolites are able to react via the Michael addition reaction mechanism with thiol groups in proteins resulting in cellular apoptosis and/or necrosis. The addition of the non-animal in chemico reactivity data (50% depletion of free glutathione) reduced the uncertainty so the read-across prediction for the straight-chain olefinic -unsaturated alcohols is deemed equivalent to a standard test. Specifically, the rat oral 90-day repeated-dose No Observed Adverse Effect Level (NOAEL) for 2-propen-1-ol of 6 mg/kg body weight bw/d in males based on increase in relative weight of liver and 25 mg/kg bw/d in females based on bile duct hyperplasia and periportal hepatocyte hypertrophy in the liver, is read across to fill data gaps for the straight-chained analogues

In silico prediction of skin metabolism and its implication in toxicity assessment

Skin, being the largest organ of the body, represents an important route of exposure, not only for the abundance of chemicals present in the environment, but also for products designed for topical application such as drugs and personal care products. Determining whether such incidental or intentional exposure poses a risk to human health requires consideration of temporal concentration, both externally and internally, in addition to assessing the chemical’s intrinsic hazard. In order to elicit a toxic response in vivo the chemical must reach its site of action in sufficient concentration, as determined by its absorption, distribution, metabolism and elimination (ADME) profile. Whilst absorption and distribution into and through skin layers have been studied for decades, only more recently has skin metabolism become a subject of intense research, now recognised as playing a key role in both toxification and detoxification processes. The majority of information on metabolic processes, however, has generally been acquired via studies performed on the liver. This paper outlines strategies that may be used to leverage current knowledge, gained from liver metabolism studies, to inform predictions for skin metabolism through understanding the differences in the enzymatic landscapes between skin and liver. The strategies outlined demonstrate how an array of in silico tools may be used in concert to resolve a significant challenge in predicting toxicity following dermal exposure. The use of in vitro methods for determining skin metabolism, both to provide further experimental data for modelling and to verify predictions is also discussed. Herein, information on skin metabolism is placed within the context of toxicity prediction for risk assessment, which requires consideration of both exposure and hazard of parent chemicals and their metabolites

Inroads to Predict in Vivo Toxicology—An Introduction to the eTOX Project

There is a widespread awareness that the wealth of preclinical toxicity data that the pharmaceutical industry has generated in recent decades is not exploited as efficiently as it could be. Enhanced data availability for compound comparison (“read-across”), or for data mining to build predictive tools, should lead to a more efficient drug development process and contribute to the reduction of animal use (3Rs principle). In order to achieve these goals, a consortium approach, grouping numbers of relevant partners, is required. The eTOX (“electronic toxicity”) consortium represents such a project and is a public-private partnership within the framework of the European Innovative Medicines Initiative (IMI). The project aims at the development of in silico prediction systems for organ and in vivo toxicity. The backbone of the project will be a database consisting of preclinical toxicity data for drug compounds or candidates extracted from previously unpublished, legacy reports from thirteen European and European operation-based pharmaceutical companies. The database will be enhanced by incorporation of publically available, high quality toxicology data. Seven academic institutes and five small-to-medium size enterprises (SMEs) contribute with their expertise in data gathering, database curation, data mining, chemoinformatics and predictive systems development. The outcome of the project will be a predictive system contributing to early potential hazard identification and risk assessment during the drug development process. The concept and strategy of the eTOX project is described here, together with current achievements and future deliverables

Potent Phototoxicity of Marine Bunker Oil to Translucent Herring Embryos after Prolonged Weathering

Pacific herring embryos (Clupea pallasi) spawned three months following the Cosco Busan bunker oil spill in San Francisco Bay showed high rates of late embryonic mortality in the intertidal zone at oiled sites. Dead embryos developed to the hatching stage (e.g. fully pigmented eyes) before suffering extensive tissue deterioration. In contrast, embryos incubated subtidally at oiled sites showed evidence of sublethal oil exposure (petroleum-induced cardiac toxicity) with very low rates of mortality. These field findings suggested an enhancement of oil toxicity through an interaction between oil and another environmental stressor in the intertidal zone, such as higher levels of sunlight-derived ultraviolet (UV) radiation. We tested this hypothesis by exposing herring embryos to both trace levels of weathered Cosco Busan bunker oil and sunlight, with and without protection from UV radiation. Cosco Busan oil and UV co-exposure were both necessary and sufficient to induce an acutely lethal necrotic syndrome in hatching stage embryos that closely mimicked the condition of dead embryos sampled from oiled sites. Tissue levels of known phototoxic polycyclic aromatic compounds were too low to explain the observed degree of phototoxicity, indicating the presence of other unidentified or unmeasured phototoxic compounds derived from bunker oil. These findings provide a parsimonious explanation for the unexpectedly high losses of intertidal herring spawn following the Cosco Busan spill. The chemical composition and associated toxicity of bunker oils should be more thoroughly evaluated to better understand and anticipate the ecological impacts of vessel-derived spills associated with an expanding global transportation network