Data quality in the human and environmental health sciences: Using statistical confidence scoring to improve QSAR/QSPR modeling

A greater number of toxicity data are becoming publicly available allowing for in silico modeling. However, questions often arise as how to incorporate data quality and how to deal with contradicting data if more than a single datum point is available for the same compound. In this study, two well-known and studied QSAR/QSPR models for skin permeability and aquatic toxicology have been investigated in the context of statistical data quality. In particular, the potential benefits of the incorporation of the statistical Confidence Scoring (CS) approach within modelling and validation. As a result, robust QSAR/QSPR models for the skin permeability coefficient and the toxicity of nonpolar narcotics to Aliivibrio fischeri assay were created. CSweighted linear regression for training and CS-weighted root mean square error (RMSE) for validation were statistically superior compared to standard linear regression and standard RMSE. Strategies are proposed as to how to interpret data with high and low CS, as well as how to deal with large datasets containing multiple entries

The read-across hypothesis and environmental risk assessment of pharmaceuticals

This article is made available through the Brunel Open Access Publishing Fund. Copyright © 2013 American Chemical Society.Pharmaceuticals in the environment have received increased attention over the past decade, as they are ubiquitous in rivers and waterways. Concentrations are in sub-ng to low μg/L, well below acute toxic levels, but there are uncertainties regarding the effects of chronic exposures and there is a need to prioritise which pharmaceuticals may be of concern. The read-across hypothesis stipulates that a drug will have an effect in non-target organisms only if the molecular targets such as receptors and enzymes have been conserved, resulting in a (specific) pharmacological effect only if plasma concentrations are similar to human therapeutic concentrations. If this holds true for different classes of pharmaceuticals, it should be possible to predict the potential environmental impact from information obtained during the drug development process. This paper critically reviews the evidence for read-across, and finds that few studies include plasma concentrations and mode of action based effects. Thus, despite a large number of apparently relevant papers and a general acceptance of the hypothesis, there is an absence of documented evidence. There is a need for large-scale studies to generate robust data for testing the read-across hypothesis and developing predictive models, the only feasible approach to protecting the environment.BBSRC Industrial Partnership Award BB/ I00646X/1 and BBSRC Industrial CASE Partnership Studentship BB/I53257X/1 with AstraZeneca Safety Health and Environment Research Programme

Compounds from Silicones Alter Enzyme Activity in Curing Barnacle Glue and Model Enzymes

Background: Attachment strength of fouling organisms on silicone coatings is low. We hypothesized that low attachment strength on silicones is, in part, due to the interaction of surface available components with natural glues. Components could alter curing of glues through bulk changes or specifically through altered enzyme activity. Methodology/Principal Findings: GC-MS analysis of silicone coatings showed surface-available siloxanes when the coatings were gently rubbed with a cotton swab for 15 seconds or given a 30 second rinse with methanol. Mixtures of compounds were found on 2 commercial and 8 model silicone coatings. The hypothesis that silicone components alter glue curing enzymes was tested with curing barnacle glue and with commercial enzymes. In our model, barnacle glue curing involves trypsin-like serine protease(s), which activate enzymes and structural proteins, and a transglutaminase which cross-links glue proteins. Transglutaminase activity was significantly altered upon exposure of curing glue from individual barnacles to silicone eluates. Activity of purified trypsin and, to a greater extent, transglutaminase was significantly altered by relevant concentrations of silicone polymer constituents. Conclusions/Significance: Surface-associated silicone compounds can disrupt glue curing and alter enzyme properties

Grouping and relative ranking of the impact potential of PBT/vPvB substances for comparative assessments in the context of socio-economic analysis under REACH

The assessment of PBT/vPvB substances under REACH may evaluate long-term exposure dynamics and impact potential. Grouping and relative ranking of PBT/vPvB substances can support comparative assessments of either several substances with the same use, or for a particular substance with different uses (emission patterns) in the context of socio-economic analysis (SEA). The aim of the grouping of PBT/vPvB substances is to classify a target chemical with respect to its similarity of properties/behaviour with chemicals with known impacts, serving as points of reference for the impact evaluation. The relative ranking of PBT/vPvB substances is based on an impact score, which captures diverse properties and effects of target substances. The impact score consists of individual scores assigned to expected environmental stocks, possible effects of PBTs/vPvBs on the environment and on human health via the environment (toxicological benchmarks), and to other specific concerns. The resulting fingerprints of concern (pattern of the individual scores) and the overall scores for impact potential can be used for comparative assessments. For example, if similar fingerprints are observed for two substances with a similar use, the total score gives an indication which substance might be less (or more) critical. For 17 case study chemicals, data on partitioning properties (log Kow, log Koa), stocks in water/sediment and soil, long range transport potential (LRTP), overall persistence (Pov), toxicological benchmark values for water and soil, CMR properties (H-phrases), endocrine disruption (ED) potential, production/emission volume, and use pattern have been collected from REACH dossiers or estimated with suitable tools. The examples illustrate the possibilities and present limitations of the grouping and relative ranking to describe and evaluate differences of PBTs/vPvB substances with regard to impact potential. Based on current knowledge, this grouping and relative ranking can guide the formation of concern-based categories for a possible read-across or comparative evaluation of impact potential of PBT/vPvB substances. Acknowledgement – This work was funded by the European Commission, Directorate-General for Internal Market, Industry, Entrepreneurship and SMEs under Contract number: 30-CE-0830972/00-26 ‘Approach for evaluation of PBTs subject to authorisation and restriction procedures in context of socio-economic analysis’