Construction of an In Silico Structural Profiling Tool Facilitating Mechanistically Grounded Classification of Aquatic Toxicants.

The performance of chemical safety assessment within the domain of environmental toxicology is often impeded by a shortfall of appropriate experimental data describing potential hazards across the many compounds in regular industrial use. In silico schemes for assigning aquatic-relevant modes or mechanisms of toxic action to substances, based solely on consideration of chemical structure, have seen widespread employment─including those of Verhaar, Russom, and later Bauer (MechoA). Recently, development of a further system was reported by Sapounidou, which, in common with MechoA, seeks to ground its classifications in understanding and appreciation of molecular initiating events. Until now, this Sapounidou scheme has not seen implementation as a tool for practical screening use. Accordingly, the primary purpose of this study was to create such a resource─in the form of a computational workflow. This exercise was facilitated through the formulation of 183 structural alerts/rules describing molecular features associated with narcosis, chemical reactivity, and specific mechanisms of action. Output was subsequently compared relative to that of the three aforementioned alternative systems to identify strengths and shortcomings as regards coverage of chemical space.

A scheme to evaluate structural alerts to predict toxicity - Assessing confidence by characterising uncertainties.

Structure-activity relationships (SARs) in toxicology have enabled the formation of structural rules which, when coded as structural alerts, are essential tools in in silico toxicology. Whilst other in silico methods have approaches for their evaluation, there is no formal process to assess the confidence that may be associated with a structural alert. This investigation proposes twelve criteria to assess the uncertainty associated with structural alerts, allowing for an assessment of confidence. The criteria are based around the stated purpose, description of the chemistry, toxicology and mechanism, performance and coverage, as well as corroborating and supporting evidence of the alert. Alerts can be given a confidence assessment and score, enabling the identification of areas where more information may be beneficial. The scheme to evaluate structural alerts was placed in the context of various use cases for industrial and regulatory applications. The analysis of alerts, and consideration of the evaluation scheme, identifies the different characteristics an alert may have, such as being highly specific or generic. These characteristics may determine when an alert can be used for specific uses such as identification of analogues for read-across or hazard identification.

Aquatic Toxicity Calculation of Mixtures: A Chemical Activity Approach Incorporating a Bioavailability Reduction Concept.

A calculation estimating the effect concentration (EL/LL50) of a water-accommodated fraction (WAF) for mixture toxicity is proposed. The method is based on chemical activity where the activity of a molecule is its effective concentration taking into account intermolecular interactions. First, the thermodynamic influence of each constituent on the solubility of the others within the mixture (i.e. the concentration of each constituent in the "loading rate") is determined. Then, the non-bioavailable fraction is determined and removed to calculate the true concentration of each constituent exerting toxicity. Finally, the loading rate is adjusted until the sum of activities of the bioavailable fractions is equal to the fraction-weighted average of toxic activity of each constituent. This process is a mechanistic interpretation of experimental WAF tests. The methodology has been validated comparing toxic loading rates of 13 reliable experimental WAF studies on fish, daphnids, and algae. The predictions were all within a factor of 2 of the study outcomes and can be considered as accurate as the laboratory studies. This is in contrast to the standard additivity method which consistently overestimates the toxicity of these mixtures by at least a factor of 2 up to over an order of magnitude or even more.

How in silico and QSAR approaches can increase confidence in environmental hazard and risk assessment.

In silico methods are typically underrated in the current risk assessment paradigm, as evidenced by the recent document from the European Chemicals Agency (ECHA) on animal alternatives, in which quantitative structure-activity relationships (QSARs) were practically used only as a last resort. Their primary use is still to provide supporting evidence for read-across strategies or to add credence to experimental results of unknown or limited validity (old studies, studies without good laboratory practices [GLPs], limited information reported, etc.) in hazard assessment, but under the pressure of increasing burdens of testing, industry and regulators alike are at last warming to them. Nevertheless, their true potential for data-gap filling and for resolving sticking points in risk assessment methodology and beyond has yet to be recognized. We postulate that it is possible to go beyond the level of simply increasing confidence to the point of using in silico approaches to accurately predict results that cannot be resolved analytically. For example, under certain conditions it is possible to obtain meaningful results by in silico extrapolation for tests that would be technically impossible to conduct in the laboratory or at least extremely challenging to obtain reliable results. The following and other concepts are explored in this article: the mechanism of action (MechoA) of the substance should be determined, as an aid verifying that the QSAR model is applicable to the substance under review; accurate QSARs should be built with high-quality data that were not only curated but also validated with expert judgment; although a rule of thumb for acute to chronic ratios appears applicable for nonpolar narcotics, it seems unlikely that a "one-value-fits-all" answer exists for other MechoAs; a holistic approach to QSARs can be employed (via reverse engineering) to help validate or invalidate an experimental endpoint value on the basis of multiple experimental studies. Integr Environ Assess Manag 2019;15:40-50. © 2018 SETAC.

Bioavailability and detoxification of cationics: II. Relationship between toxicity and CEC of cationic surfactants on Caenorhabditis elegans (Nematoda) in artificial and natural substrates.

The toxicity of the dialkyl quat, didecyldimethylammonium bromide (DDAB), was used as a typical quaternary ammonium compound in studies investigating the role of sorption in reducing DDAB bioavailability in sediment and soil for natural and artificial substrates. Fatty acid derivatives are known to interact ionically with negative charged particles such as clays, humic and fulvic acids, dramatically reducing their bioavailability. Sorption potential was measured using cationic exchange capacities (CEC). The CEC of the substrates was correlated with toxicity of DDAB to the nematode Caenorhabditis elegans considered to be representative of soil and sediment dwelling, free-living nematodes in terms of its sensitivity, size and feeding strategy. Decreased toxicity was found with increasing CEC for both laboratory and field substrates when tested under both soil and sediment conditions and QSARs developed. Testing under soil or sediment conditions had less impact on the toxicity than the CEC of the soil/sediment or whether the substrate was artificial or natural. Habitat preferences were observed during a test in which nematodes were placed into substrates with different CECs. The worms favoured mid-range CECs. Similar preference behaviour may be expected in the environment and a threshold CEC for likely presence of nematodes in a substrate is proposed. Coupled with the substrate toxicity QSAR, threshold CEC preference can be used to provide a no observed effect concentration for DDAB. Expressed as a molar fraction of the CEC, the QSAR obtained for DDAB may be extrapolable to other fatty amine derivatives. If supported by further experimentation and complemented with data from other sediment and soil dwellers the QSAR and threshold CEC value can be validated for use in future regulatory risk assessments of fatty amine derivatives.

Sources and prevalence of pentachlorobenzene in the environment.

There are no longer any large scale uses of pentachlorobenzene (PeCB). Current emissions of PeCB to the environment are estimated to be about 121000kgy(-1), based on published information. The largest sources appear to be combustion of solid wastes, 32000kgy(-1), biomass burning, 45000kgy(-1) with degradation of an agricultural fungicide, quintozene, contributing 26000kgy(-1) and industrial releases less important. PeCB has been measured in many environmental media over the past 35 years. Low but detectable concentrations of PeCB have been reported in the atmosphere, sediments and biota in remote areas of the world. Calculations using a global distribution model are consistent with the estimate of approximately 100000kgy(-1) global PeCB emissions. Concentrations of PeCB in the environment have declined with a 90% decrease of PeCB concentrations in herring gull eggs from Lake Superior, Canada since 1979.