| 1. |
- Malkiewicz, Katarzyna, et al.
(author)
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Human experts' judgment of chemicals reactivity for identification of hazardous chemicals
- 2009
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In: Toxicology Letters. - : Elsevier BV. - 0378-4274 .- 1879-3169. ; 189, s. S243-S243
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Journal article (other academic/artistic)abstract
- The development of non-testing approaches for the identification of chemicals with the potential to cause environmental hazards, have gained increased attention. In this study the hypothesis that experts’ judgement of chemical reactivity could be used for this purpose has been tested. The judgments of chemical reactivity for 200 organic chemicals, based on their molecular structure were performed by four senior organic and environmental chemists. Potentials for reactivity (namely: oxidative/reductive reactivity, hydrolysis, direct photolysis, reactivity towards radicals) were scored on the 1– scale. Both the experts’ individual judgment, and a compromised judgment after joint discussion for clarification of cases with divergent opinions, was analysed. Furthermore we searched for relations between the expert judgement data and: (a) the chemical characteristics representedby 40 chemical descriptors using partial least squares regression (PLS), and (b) experimental and in silico data for different toxicological and physico-chemical end-points. The results of on-going analyses indicate that for the majority of the chemicals, the individual judgments differed significantly between experts but after discussion among the experts for clarification, the judgments becamemuch more concurrent. The relation between averaged experts’ predicted photolytic degradation potential and chemical characteristic based on a PLS model (with three significant components explaining 76% of the variation) was found. We have also found that in the group of the chemicals with the higher score of the experts judged oxidative reactivity there was higher percentage of biodegradable chemicals when compar
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| 2. |
- Molander, Linda, et al.
(author)
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Are chemicals in articles an obstacle for reaching environmental goals? : Missing links in eu chemical management
- 2012
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In: Science of the Total Environment. - : Elsevier BV. - 0048-9697 .- 1879-1026. ; 435, s. 280-289
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Journal article (peer-reviewed)abstract
- It is widely acknowledged that the management of risks associated with chemicals in articles needs to be improved. The EU environmental policy states that environmental damage should be rectified at source. It is therefore motivated that the risk management of substances in articles also takes particular consideration to those substances identified as posing a risk in different environmental compartments. The primary aim of the present study was to empirically analyze to what extent the regulation of chemicals in articles under REACH is coherent with the rules concerning chemicals in the Sewage Sludge Directive (SSD) and the Water Framework Directive (WFD). We also analyzed the chemical variation of the organic substances regulated under these legislations in relation to the most heavily used chemicals. The results show that 16 of 24 substances used in or potentially present in articles and regulated by the SSD or the WFD are also identified under REACH either as a substance of very high concern (SVHC) or subject to some restrictions. However, for these substances we conclude that there is limited coherence between the legislations, since the identification as an SVHC does not in itself encompass any use restrictions, and the restrictions in REACH are in many cases limited to a particular use, and thus all other uses are allowed. Only a minor part of chemicals in commerce is regulated and these show a chemical variation that deviates from classical legacy pollutants. This warrants new tools to identify potentially hazardous chemicals in articles. We also noted that chemicals monitored in the environment under the WFD deviate in their chemistry from the ones regulated by REACH. In summary, we argue that to obtain improved resource efficiency and a sustainable development it is necessary to minimize the input of chemicals identified as hazardous to health or the environment into articles.
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| 3. |
- Rybacka, Aleksandra, 1987-
(author)
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A step forward in using QSARs for regulatory hazard and exposure assessment of chemicals
- 2016
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Doctoral thesis (other academic/artistic)abstract
- According to the REACH regulation chemicals produced or imported to the European Union need to be assessed to manage the risk of potential hazard to human health and the environment. An increasing number of chemicals in commerce prompts the need for utilizing faster and cheaper alternative methods for this assessment, such as quantitative structure-activity or property relationships (QSARs or QSPRs). QSARs and QSPRs are models that seek correlation between data on chemicals molecular structure and a specific activity or property, such as environmental fate characteristics and (eco)toxicological effects.The aim of this thesis was to evaluate and develop models for the hazard assessment of industrial chemicals and the exposure assessment of pharmaceuticals. In focus were the identification of chemicals potentially demonstrating carcinogenic (C), mutagenic (M), or reprotoxic (R) effects, and endocrine disruption, the importance of metabolism in hazard identification, and the understanding of adsorption of ionisable chemicals to sludge with implications to the fate of pharmaceuticals in waste water treatment plants (WWTPs). Also, issues related to QSARs including consensus modelling, applicability domain, and ionisation of input structures were addressed.The main findings presented herein are as follows:QSARs were successful in identifying almost all carcinogens and most mutagens but worse in predicting chemicals toxic to reproduction.Metabolic activation is a key event in the identification of potentially hazardous chemicals, particularly for chemicals demonstrating estrogen (E) and transthyretin (T) related alterations of the endocrine system, but also for mutagens. The accuracy of currently available metabolism simulators is rather low for industrial chemicals. However, when combined with QSARs, the tool was found useful in identifying chemicals that demonstrated E- and T- related effects in vivo.We recommend using a consensus approach in final judgement about a compound’s toxicity that is to combine QSAR derived data to reach a consensus prediction. That is particularly useful for models based on data of slightly different molecular events or species.QSAR models need to have well-defined applicability domains (AD) to ensure their reliability, which can be reached by e.g. the conformal prediction (CP) method. By providing confidence metrics CP allows a better control over predictive boundaries of QSAR models than other distance-based AD methods.Pharmaceuticals can interact with sewage sludge by different intermolecular forces for which also the ionisation state has an impact. Developed models showed that sorption of neutral and positively-charged pharmaceuticals was mainly hydrophobicity-driven but also impacted by Pi-Pi and dipole-dipole forces. In contrast, negatively-charged molecules predominantly interacted via covalent bonding and ion-ion, ion-dipole, and dipole-dipole forces.Using ionised structures in multivariate modelling of sorption to sludge did not improve the model performance for positively- and negatively charged species but we noted an improvement for neutral chemicals that may be due to a more correct description of zwitterions. Overall, the results provided insights on the current weaknesses and strengths of QSAR approaches in hazard and exposure assessment of chemicals. QSARs have a great potential to serve as commonly used tools in hazard identification to predict various responses demanded in chemical safety assessment. In combination with other tools they can provide fundaments for integrated testing strategies that gather and generate information about compound’s toxicity and provide insights of its potential hazard. The obtained results also show that QSARs can be utilized for pattern recognition that facilitates a better understanding of phenomena related to fate of chemicals in WWTP.
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| 4. |
- Rybacka, Aleksandra, et al.
(author)
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Identifying potential endocrine disruptors among industrial chemicals and their metabolites - development and evaluation of in silico tools
- 2015
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In: Chemosphere. - : Elsevier BV. - 0045-6535 .- 1879-1298. ; 139, s. 372-378
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Journal article (peer-reviewed)abstract
- The aim of this study was to improve the identification of endocrine disrupting chemicals (EDCs) by developing and evaluating in silico tools that predict interactions at the estrogen (E) and androgen (A) receptors, and binding to transthyretin (T). In particular, the study focuses on evaluating the use of the EAT models in combination with a metabolism simulator to study the significance of bioactivation for endocrine disruption. Balanced accuracies of the EAT models ranged from 77-87%, 62-77%, and 65-89% for E-, A-, and T-binding respectively. The developed models were applied on a set of more than 6000 commonly used industrial chemicals of which 9% were predicted E- and/or A-binders and 1% were predicted T-binders. The numbers of E- and T-binders increased 2- and 3-fold, respectively, after metabolic transformation, while the number of A-binders marginally changed. In-depth validation confirmed that several of the predicted bioactivated E- or T-binders demonstrated in vivo estrogenic activity or influenced blood levels of thyroxine in vivo. The metabolite simulator was evaluated using in vivo data from the literature which showed a 50% accuracy for studied chemicals. The study stresses, in summary, the importance of including metabolic activation in prioritization activities of potentially emerging contaminants.
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| 5. |
- Rybacka, Aleksandra, et al.
(author)
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On the Use of In Silico Tools for Prioritising Toxicity Testing of the Low-Volume Industrial Chemicals in REACH
- 2014
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In: Basic & Clinical Pharmacology & Toxicology. - : Wiley. - 1742-7835 .- 1742-7843. ; 115:1, s. 77-87
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Research review (peer-reviewed)abstract
- This study was conducted to evaluate the utility of a selection of commercially and freely available non-testing tools and to analyse how REACH registrants can apply these as prioritisation tool for low-volume chemicals. The analysis was performed on a set of organic industrial chemicals and pesticides with extensive peer-reviewed risk assessment data. Analysed in silico model systems included Derek Nexus, Toxtree, QSAR Toolbox, LAZAR, TEST and VEGA, and results from these were compared with expert-judged risk classification according to the classifying, labelling and packaging (CLP) regulation. The most reliable results were obtained for carcinogenicity; however, less reliable predictions were derived for mutagenicity and reproductive toxicity. A group of compounds frequently predicted as false negatives was identified. These were relatively small molecules with low structural complexity, for example benzene derivatives with hydroxyl-, amino- or aniline-substituents. A rat liver S9 metabolite simulator was applied to illustrate the importance of considering metabolism in the risk assessment procedure. We also discuss outcome of combining predictions from multiple model systems and advise how to apply in silico tools. These models are proposed to be used to prioritise low-volume chemicals for testing within the REACH legislation, and we conclude that further guidance is needed so that industry can select and apply models in a reliable, systematic and transparent way.
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