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REACH (registration, evaluation, authorisation and restriction of chemicals) regulation requires that all the chemicals produced or imported in Europe above 1 tonne/year are registered. To register a chemical, physicochemical, toxicological and ecotoxicological information needs to be reported in a dossier. REACH promotes the use of alternative methods to replace, refine and reduce the use of animal (eco)toxicity testing. Within the EU OSIRIS project, integrated testing strategies (ITSs) have been developed for the rational use of non-animal testing approaches in chemical hazard assessment. Here we present an ITS for evaluating the bioaccumulation potential of organic chemicals. The scheme includes the use of all available data (also the non-optimal ones), waiving schemes, analysis of physicochemical properties related to the end point and alternative methods (both in silico and in vitro). In vivo methods are used only as last resort. Using the ITS, in vivo testing could be waived for about 67% of the examined compounds, but bioaccumulation potential could be estimated on the basis of non-animal methods. The presented ITS is freely available through a web tool., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

This paper presents an inventory of in silico screening tools to identify substance properties of concern under the European chemicals' legislation REACH. The objective is to support the selection and implementation of appropriate tools as building blocks within integrated testing strategies (ITS). The relevant concerns addressed are persistence, bioaccumulation potential, acute and long-term aquatic toxicity, PBT/vPvB properties ((very) persistent, (very) bioaccumulative, toxic), CMR (carcinogenicity, mutagenicity, reproductive toxicity), endocrine disruption and skin sensitisation. The inventory offers a comparative evaluation of methods with respect to the underlying algorithms (how does the method work?) and the applicability domains (when does the method work?) as well as their limitations (when does the method not work?). The inventory explicitly addresses the reliability of predictions of different in silico models for diverse chemicals by applicability domain considerations. The confidence in predictions can be greatly improved by consensus modelling that allows for taking conflicting results into account. The inventory is complemented by a brief discussion of socio-economic tools for assessing the potential efficiency gains of using in silico methods compared to traditional in vivo testing of chemical hazards., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background and Scope: Predictive toxicology, particularly quantitative structure-activity relationships (QSARs), require classification of chemicals by mode of action (MOA). MOA is, however, not a constant property of a compound but it varies between species and may change with concentration and duration of exposure. A battery of MOA-specific in-vitro and low-complexity assays, featuring biomolecular targets for major classes of environmental pollutants, provides characteristic responses for (1.) classification of chemicals by MOA, (2.) identification of (eco)toxicity profiles of chemicals, (3.) identification of chemicals with specific MOAs, (4.) indication of most sensitive species, (5.) identification of chemicals that are outliers in QSARs and (6.) selection of appropriate QSARs for predictions., Methods: Chemicals covering nine distinct modes of toxic action (non-polar non-specific toxicants (n=14), polar non-specific toxicants (n=18), uncouplers of oxidative phosphorylation (n=25), inhibitors of photosynthesis (n=15), inhibitors of acetylcholinesterase (n=14), inhibitors of respiration (n=3), thiol-alkylating agents (n=9), reactives (irritants) (n=8), estrogen receptor agonists (n=9)) were tested for cytotoxicity in the neutralred assay, oxygen consumption in isolated mitochondria, oxygen production in algae, inhibition of AChE, reaction with GSH and activity in the yeast estrogen receptor assay. Data on in-vivo aquatic toxicity (LC50, EC50) towards fish, daphnids, algae and bacteria were collected from the literature for reasons of comparison and reference scaling., Results and Discussion: In the MOA-specific in-vitro test battery, most test chemicals are specifically active at low concentrations, though multiple effects do occur. Graphical and statistical evaluation of the individual classes versus MOA 1 (non-polar non-specific toxicants) identifies interactions related to predominant MOA. Discriminant analyses (DA) on subsets of the data revealed correct classifications between 70% (in-vivo data) and >90% (in-vitro data). Functional similarity of chemical substances is defined in terms of their (eco)toxicity profiles. Within each MOA class, the compounds share some properties related to the rate-limiting interactions, e.g., steric fit to the target site and/or reactivity with target biomolecules, revealing a specific pattern (fingerprint) of characteristic effects., Conclusion: The successful discrimination of toxicant classes by MOA is based on comprehensive characterization of test chemicals' properties related to interactions with target sites. The suite of aquatic in-vivo tests using fish, daphnids, algae and bacteria covers most acute effects, whilst long-term (latent) impacts are generally neglected. With the MOA-specific in-vitro test battery such distinctions are futile, because it focuses on isolated targets, i.e. it indicates the possible targets of a chemical regardless of the timescale of effects. The data analysis indicates that the in-vitro battery covers most effects in vivo and moreover provides additional aspects of the compounds' MOA., Recommendation and Perspective: Translating in-vitro effects to in-vivo toxicity requires combining physiological and chemical knowledge about underlying processes. Comparison of the specific in-vitro effects of a compound with the respective sensitivities of aquatic organisms indicates particularly sensitive species. Classifications of toxicants by MOA based on physicochemical descriptors provides insight to interactions and directs to mechanistic QSARs.

Background: Replacing hazardous chemicals with safer alternatives is essential for a toxic-free environment. To avoid regrettable substitution, a comparison of the entire spectrum of potential impacts of the candidate for substitution with those of the available alternatives is required. A particular challenge is to also capture yet unknown long-term impacts of (very) persistent chemicals, including but not limited to PBT and CMR properties. Results: For a flexible and transparent comparative ranking of the impact potential of chemical alternatives, we propose a concern-based scoring scheme (Scoring scheme for Comparative Ranking of chemical Alternatives, SCoRA). The approach accounts for hazards due to ecotoxicity in water/sediment and soil, and effects on human health such as CMR properties and endocrine disruption. This is combined with exposure-related information in terms of expected environmental pollution stock levels. The SCoRA approach is illustrated with case study chemicals of very high concern (15 SVHC, mostly PBT, representing different chemical classes with different modes of bioaccumulation and toxicity). A comparison of PBT substances reveals that SCoRA goes well beyond binary screening criteria (PBT: yes/no), showing that PBT substances are all of very high concern, although their impact profiles can be substantially different. Ordinal scores support a detailed characterisation of their potential for long-term impacts. Furthermore, SCoRA enables a coherent comparative assessment of substances with different primary concerns, for example PBTness and endocrine disruption. Conclusions: SCoRA complements existing and established tools such as comparative risk assessment. It is particularly useful, when, for example, only limited data are available or when risk assessment is not feasible, as in the case of persistent chemicals. A strength of SCoRA is that the relative contributions of the impact components determining the concern can be visualised with a heatmap and fingerprints. This facilitates communication among scientists, regulators, risk managers, stakeholders and the public. [ABSTRACT FROM AUTHOR]