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Background: The increasing development and use of nanobiomaterials raises questions about their potential adverse effects on the environment after excretion and release. Published ecotoxicological data was searched for five polymeric nanobiomaterials [chitosan, polylactic acid (PLA), polyacrylonitrile (PAN), polyhydroxyalkanoates (PHA), and poly(lactic-glycolic acid) (PLGA)] and one inorganic nanobiomaterial [hydroxyapatite (HAP)] to evaluate the environmental hazards for freshwater and soil using a meta-analysis. If enough data was available, a probabilistic species sensitivity distribution (pSSD) and from this a predicted no effect concentration (PNEC) was calculated. If only one data point was available, a PNEC was calculated based on the most sensitive endpoint. Each material was classified either as "nano" or "non-nano", depending on the categorization in the original articles. When the original article specified that the material consisted of nanoparticles, the material was classified as nano; when nothing was mentioned, the material was classified as "non-nano"., Results: For PLA, PHA and PLGA, no published data on ecotoxicity was found and therefore no hazard assessment could be conducted. In soils, HAP was found to have the lowest PNEC with 0.3 mg/kg, followed by PAN and chitosan. In freshwater, chitosan was found to have the lowest PNEC with 5 µg/l, followed by nano-chitosan, HAP and PAN., Conclusion: Compared with other common pollutants, even the most sensitive of the selected nanobiomaterials, chitosan, is less toxic than engineered nanomaterials such as nano-ZnO and nano-Ag, some common antibiotics, heavy metals or organic pollutants such as triclosan. Given the current knowledge, the nanobiomaterials covered in this work therefore pose only little or no environmental hazard.

A nationwide investigation was carried out to evaluate the geochemical characteristics and environmental impacts of red mud and leachates from the major alumina plants in China. The chemical and mineralogical compositions of red mud were investigated, and major, minor, and trace elements in the leachates were analyzed. The mineral and chemical compositions of red mud vary over refining processes (i.e., Bayer, sintering, and combined methods) and parental bauxites. The main minerals in the red mud are quartz, calcite, dolomite, hematite, hibschite, sodalite, anhydrite, cancrinite, and gibbsite. The major chemical compositions of red mud are Al, Fe, Si, Ca, Ti, and hydroxides. The associated red mud leachate is hyperalkaline (pH > 12), which can be toxic to aquatic life. The concentrations of Al, Cl - , F - , Na, NO₃ 2- , and SO₄ 2- in the leachate exceed the recommended groundwater quality standard of China by up to 6637 times. These ions are likely to increase the salinization of the soil and groundwater. The minor elements in red mud leachate include As, B, Ba, Cr, Cu, Fe, Ni, Mn, Mo, Ti, V, and Zn, and the trace elements in red mud leachate include Ag, Be, Cd, Co, Hg, Li, Pb, Sb, Se, Sr, and Tl. Some of these elements have the concentration up to 272 times higher than those of the groundwater quality standard and are toxic to the environment and human health. Therefore, scientific guidance is needed for red mud management, especially for the design of the containment system of the facilities.

[Introduction] Seven smoke constituents, including hydrogen cyanide (HCN), ammonia (NH 3 ), phenol, benzo[α]pyrene (B[a]P), carbon monoxide (CO)¸ crotonaldehyde, and 4-(methylnitrosamino)-1- (3-pyridyl)-1-butanone (NNK), are proposed be the most relevant constituents for smoking-related diseases. [Methods] Different combinations of leaf stalk positions, varieties and locations were used to create variable chemistry of cigarette filler and smoke. Experimental cigarettes were measured for emission level of seven smoke toxicants and content of seventy-three filler components. [Results] The ranges of coefficient of variation (CV) for seven smoke toxicants were 15.43%-43.15%. The emission pattern of NNK and crotonaldehyde were different from that of other five smoke toxicants. Most of the seven smoke toxicants were influenced in following order: stalk position > location > variety. The leaf constitutes closely correlated with seven smoke toxicants were analyzed. [Conclusions] The results showed that seven toxicants were significantly influenced by leaf position and location, and closely correlated with leaf components, such as potassium, malate and alkaloid contents. The results provide useful and comprehensive information on the affecting factors and correlating leaf constituents for the variations of seven smoke toxicants., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: In 2006, titanium dioxide and carbon black were classified by IARC as "possibly carcinogenic to humans" and in 2017 the European Chemicals Agency's (ECHA) Committee for Risk Assessment concluded titanium dioxide meets the criteria to be classified as suspected of causing cancer (category 2, through the inhalation route). These classifications were based primarily on the occurrence of lung cancer in rats exposed chronically to high concentrations of these materials, as no such responses have been observed in other animal species similarly exposed. After the EU classification of titanium dioxide, it was suggested that Poorly Soluble particles of Low Toxicity (PSLTs) can be evaluated as a group., Main Body: To better understand the current state of scientific opinion, we sought perspective from several international experts on topics relevant to the classification of carbon black; titanium dioxide; and, the potential future classification of PSLTs. Areas discussed included: grouping of PSLTs; the relevance of rat lung cancer responses to high concentrations of PSLTs; and, clearance overload and implications for interpretation of inhalation toxicology studies. We found there were several areas where a large majority of experts, including ourselves, agreed. These included concerns on the grouping of PSLT and the definition of clearance overload. Regarding the extrapolation of PSLT associated lung cancer in rats there were some strongly held differences, although most experts questioned the relevance when excessive exposures which overwhelm lung clearance were required., Short Conclusion: Given the ongoing discussion on PSLT classification and safety, we believe it is important to re-activate the public debate including experts and stakeholders. Such an open discussion would serve to formally document where scientific consensus and differences exist. This could form the basis for design of future safety programs and safety assessments.

Computational approaches are increasingly used to predict toxicity due, in part, to pressures to find alternatives to animal testing. Read-across is the "new paradigm" which aims to predict toxicity by identifying similar, data rich, source compounds. This assumes that similar molecules tend to exhibit similar activities i.e. molecular similarity is integral to read-across. Various of molecular fingerprints and similarity measures may be used to calculate molecular similarity. This study investigated the value and concordance of the Tanimoto similarity values calculated using six widely used fingerprints within six toxicological datasets. There was considerable variability in the similarity values calculated from the various molecular fingerprints for diverse compounds, although they were reasonably concordant for homologous series acting via a common mechanism. The results suggest generic fingerprint-derived similarities are likely to be optimally predictive for local datasets, i.e. following sub-categorisation. Thus, for read-across, generic fingerprint-derived similarities are likely to be most predictive after chemicals are placed into categories (or groups), then similarity is calculated within those categories, rather than for a whole chemically diverse dataset., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The increasing nanomedicine usage has raised concerns about their possible impact on human health. Present evaluation strategies for nanomaterials rely on a case-by-case hazard assessment. They take into account material properties, biological interactions, and toxicological responses. Authorities have also emphasized that exposure route and intended use should be considered in the safety assessment of nanotherapeutics. In contrast to an individual assessment of nanomaterial hazards, we propose in the present work a novel and unique evaluation strategy designed to uncover potential adverse effects of such materials. We specifically focus on spherical engineered nanoparticles used as parenterally administered nanomedicines. Standardized assay protocols from the US Nanotechnology Characterization Laboratory as well as the EU Nanomedicine Characterisation Laboratory can be used for experimental data generation. We focus on both cellular uptake and intracellular persistence as main indicators for nanoparticle hazard potentials. Based on existing regulatory specifications defined by authorities such as the European Medicines Agency and the United States Food and Drug Administration, we provide a robust framework for application-oriented classification paired with intuitive decision making. The Hazard Evaluation Strategy (HES) for injectable nanoparticles is a three-tiered concept covering physicochemical characterization, nanoparticle (bio)interactions, and hazard assessment. It is cost-effective and can assist in the design and optimization of nanoparticles intended for therapeutic use. Furthermore, this concept is designed to be adaptable for alternative exposure and application scenarios. To the knowledge of the authors, the HES is unique in its methodology based on exclusion criteria. It is the first hazard evaluation strategy designed for nanotherapeutics.

The implementation of nonanimal approaches is of particular importance to regulatory agencies for the prediction of potential hazards associated with acute exposures to chemicals. This work was carried out in the framework of an international modeling initiative organized by the Acute Toxicity Workgroup (ATWG) of the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) with the participation of 32 international groups across government, industry, and academia. Our contribution was to develop a multifingerprints similarity approach for predicting five relevant toxicology endpoints related to the acute oral systemic toxicity that are: the median lethal dose (LD50) point prediction, the "nontoxic" (LD50 > 2000 mg/kg) and "very toxic" (LD50<50 mg/kg) binary classification, and the multiclass categorization of chemicals based on the United States Environmental Protection Agency and Globally Harmonized System of Classification and Labeling of Chemicals schemes. Provided by the ICCVAM's ATWG, the training set used to develop the models consisted of 8944 chemicals having high-quality rat acute oral lethality data. The proposed approach integrates the results coming from a similarity search based on 19 different fingerprint definitions to return a consensus prediction value. Moreover, the herein described algorithm is tailored to properly tackling the so-called toxicity cliffs alerting that a large gap in LD50 values exists despite a high structural similarity for a given molecular pair. An external validation set made available by ICCVAM and consisting in 2896 chemicals was employed to further evaluate the selected models. This work returned high-accuracy predictions based on the evaluations conducted by ICCVAM's ATWG.

The use of non-testing strategies like read-across in the hazard assessment of chemicals and nanomaterials (NMs) is deemed essential to perform the safety assessment of all NMs in due time and at lower costs. The identification of physicochemical (PC) properties affecting the hazard potential of NMs is crucial, as it could enable to predict impacts from similar NMs and outcomes of similar assays, reducing the need for experimental (and in particular animal) testing. This manuscript presents a review of approaches and available case studies on the grouping of NMs to read-across hazard endpoints. We include in this review grouping frameworks aimed at identifying hazard classes depending on PC properties, hazard classification modules in control banding (CB) approaches, and computational methods that can be used for grouping for read-across. The existing frameworks and case studies are systematically reported. Relevant nanospecific PC properties taken into account in the reviewed frameworks to support grouping are shape and surface properties (surface chemistry or reactivity) and hazard classes are identified on the basis of biopersistence, morphology, reactivity, and solubility.

Today's state-of-the-art cell sorting flow cytometers are equipped with aerosol containment systems designed to evacuate aerosols from the sort chamber during a sort. This biosafety device is especially important when the sort operator is sorting infectious or potentially infections samples. Hence, it is critical to evaluate the performance for this system in normal operation and in "failure" mode to determine the efficacy of containment. In the past decade, the most popular published method for evaluating containment has been the Glo-Germ bead procedure. These highly fluorescent and multisize particles can easily be detected on a microscope slide and enumerated using a fluorescent microscope. Collecting particles on this slide is accomplished using an Aerotech impactor. This sampler collects potentially escaping aerosols from the sort chamber before enumerating any particles. Although the Glo-Germ procedure has been adopted by many labs, there are several drawbacks with the procedure that have limited its adoption by cell sorter laboratories: The Aerotech impactor is a reusable device that requires rigorous cleaning between measurements. The surface area of the collection slide is large and difficult to scan on a fluorescence microscope. These beads produce a wide variation in sizes resulting in inconsistency in flow rates. Here, we describe a novel and replacement method utilizing a Cyclex-d impactor and Dragon Green beads. This method was compared for sensitivity of detection of escaped aerosols with a published method for aerosol detection which utilizes a UV-APS aerodynamic particle sizer and a UV-excitable dye. One of the advantages of the Cyclex-d system is the narrow-defined field of collection as compared to the standard Glo-Germ bead procedure, this means a smaller sampling area is used in the Cyclex-d impactor as compared to the AeroTech impactor. In addition, the sensitivity of detection was found to be better using the Cyclex-d collection device as compared to the standard Glo-Germ bead procedure. © 2018 International Society for Advancement of Cytometry., (© 2018 International Society for Advancement of Cytometry.)

Per- and polyfluoroalkyl substances (PFASs) are a group of fluorinated substances of interest to researchers, regulators, and the public due to their widespread presence in the environment. A few PFASs have comparatively extensive amounts of human epidemiological, exposure, and experimental animal toxicity data (e.g., perfluorooctanoic acid), whereas little toxicity and exposure information exists for much of the broader set of PFASs. Given that traditional approaches to generate toxicity information are resource intensive, new approach methods, including in vitro high-throughput toxicity (HTT) testing, are being employed to inform PFAS hazard characterization and further ( in vivo ) testing. The U.S. Environmental Protection Agency (EPA) and the National Toxicology Program (NTP) are collaborating to develop a risk-based approach for conducting PFAS toxicity testing to facilitate PFAS human health assessments. This article describes the construction of a PFAS screening library and the process by which a targeted subset of 75 PFASs were selected. Multiple factors were considered, including interest to the U.S. EPA, compounds within targeted categories, structural diversity, exposure considerations, procurability and testability, and availability of existing toxicity data. Generating targeted HTT data for PFASs represents a new frontier for informing priority setting. https://doi.org/10.1289/EHP4555.

Raman spectra of the different ecotoxicants such as perfluorooctane sulfonate acid, organotin compounds of different families tributyl-, and triphenyl-, as well as chemically close compounds belonging to the same family - such as mono-, di-, and tributyl organotin compounds were analyzed. The comprehensive Raman spectra analysis allowed suggesting the identification scheme for clear recognition of the toxins family and the following intra-group specification. Possibility of unambiguous toxins detection and identification was demonstrated also for complex mixtures of various toxins on a base of control of characteristic peak groups, which can be considered as Raman fingerprints of the listed environmentally hazardous substances., (Copyright © 2018. Published by Elsevier B.V.)

Emission of hazardous trace elements (HTEs) from energy production is receiving much attention due to concerns about the toxicity to the ecosystem and human health. This study presented new field measurement data on the HTEs partitioning behavior and size-segregated elemental compositions of gaseous particular matter (PM) generated from a commercial circulating fluidized bed (CFB) power plant. Mineralogical and morphological characteristics of combustion ash and PM 2.5 (particle diameter less than 2.5 μm) were determined by X-ray diffractometer (XRD) and scanning electron microscopy with energy dispersive X-ray spectroscopy (SEM/EDS). Functional groups alteration during CFB combustion was characterized by Fourier transform infrared spectroscopy (FTIR). The presence of aliphatic hydrogen at 2910 cm -1 and 2847 cm -1 in the PM 2.5 suggested that the aliphatic carbon-rich volatiles were absorbed on the fine particles with large surface area. Fine fly ash (PM 2.5 ) occurred as irregular glass particles or/and as unburned carbon. The typical irregular particles were mainly composed of Al-Si-Ca or Al-Si-Fe phases. The enrichment behavior of HTEs was determined for the airborne size-segregated particular matter. Elemental occurrences, combustion temperature, unburnt carbon, and limestone additives during CFB combustion were critical in the transformation behavior of HTEs. The total potentially mobile pollutants that exit the CFB power plant every year were estimated as follows: 0.22 tons of Cr, 0.12 tons of Co, 0.73 tons of Ni, 0.04 tons of As, 0.07 tons of Se, 3.95 kg of Cd, and 3.34 kg of Sb., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: An increasing number of manufactured nanomaterials (NMs) are being used in industrial products and need to be registered under the REACH legislation. The hazard characterisation of all these forms is not only technically challenging but resource and time demanding. The use of non-testing strategies like read-across is deemed essential to assure the assessment of all NMs in due time and at lower cost. The fact that read-across is based on the structural similarity of substances represents an additional difficulty for NMs as in general their structure is not unequivocally defined. In such a scenario, the identification of physicochemical properties affecting the hazard potential of NMs is crucial to define a grouping hypothesis and predict the toxicological hazards of similar NMs. In order to promote the read-across of NMs, ECHA has recently published "Recommendations for nanomaterials applicable to the guidance on QSARs and Grouping", but no practical examples were provided in the document. Due to the lack of publicly available data and the inherent difficulties of reading-across NMs, only a few examples of read-across of NMs can be found in the literature. This manuscript presents the first case study of the practical process of grouping and read-across of NMs following the workflow proposed by ECHA., Methods: The workflow proposed by ECHA was used and slightly modified to present the read-across case study. The Read-Across Assessment Framework (RAAF) was used to evaluate the uncertainties of a read-across within NMs. Chemoinformatic techniques were used to support the grouping hypothesis and identify key physicochemical properties., Results: A dataset of 6 nanoforms of TiO 2 with more than 100 physicochemical properties each was collected. In vitro comet assay result was selected as the endpoint to read-across due to data availability. A correlation between the presence of coating or large amounts of impurities and negative comet assay results was observed., Conclusion: The workflow proposed by ECHA to read-across NMs was applied successfully. Chemoinformatic techniques were shown to provide key evidence for the assessment of the grouping hypothesis and the definition of similar NMs. The RAAF was found to be applicable to NMs.

For an electronic cigarette (e-cigarette) aerosol with known total particulate matter concentration (TPM, μg/m 3 ), predictions of the fractions of some compound i in the gas and particle phases ( f g, i and f p, i ) at equilibrium can be made based on K p, i (m 3 /μg), the compound-dependent gas/particle partitioning equilibrium constant. f g, i and f p, i affect the modes and locations of deposition in the respiratory tract. K p, i depends inversely on (1) the pure compound liquid vapor pressure ( p L, i o ), (2) mole fraction activity coefficient (ζ i ) in the absorbing liquid, and (3) mean molecular weight of the absorbing liquid (MW). K p, i values were measured at 20 °C for 32 compounds as spiked into simulated e-cigarette liquids prepared as 50/50 mixtures (by weight) of propylene glycol (PG) and glycerol (GL). K p, i values at 37 °C were estimated. The 32 compounds were nicotine (in free-base form), seven toxicants (propanal, acetone, hydroxyacetone, benzene, toluene, p-xylene, and ethylbenzene), and 24 flavor chemicals (2,3-pentanedione ("acetyl propionyl"), isobutyl acetate, ethyl butyrate, butyl butyrate, isoamyl acetate, 2,3-dimethylpyrazine, 3-methyl-1-butanol, limonene, 2,3,5-trimethylpyrazine, p-cymene, benzaldehyde, ( Z)-3-hexen-1-ol, menthol, 2-acetylpyrrole, benzyl alcohol, methyl salicylate, cinnamaldehyde, methyl anthranilate, (+)-aromadendrene, cinnamyl alcohol, methyl cinnamate, maltol, ethyl maltol, and coumarin). The measured log K p, i values were found to be generally correlated with literature values of log p L, i o ; the scatter is caused by variation in ζ i between ∼1 and ∼1000. K p measurements were attempted, but values were not reported for acetaldehyde, 2,3-butanedione (diacetyl), vanillin, and ethyl vanillin. Acetaldehyde was found to form significant amounts of its cyclic trimer and cyclic tetramer; for diacetyl, the evidence suggested significant amounts of reaction products, possibly hemiketals and ketals with PG/GL, and for vanillin and ethyl vanillin, the K p values are large and accordingly more difficult to measure. f g values are calculated using a range of K p and TPM values.

Within the EU FP-7 GUIDEnano project, a methodology was developed to systematically quantify the similarity between a nanomaterial (NM) that has been tested in toxicity studies and the NM for which risk needs to be evaluated, for the purpose of extrapolating toxicity data between the two materials. The methodology is a first attempt to use current knowledge on NM property-hazard relationships to develop a series of pragmatic and systematic rules for assessing NM similarity. Moreover, the methodology takes into account the practical feasibility, in that it is based on generally available NM characterization information. In addition to presenting this methodology, the lessons learnt and the challenges faced during its development are reported here. We conclude that there is a large gap between the information that is ideally needed and its application to real cases. The current database on property-hazard relationships is still very limited, which hinders the agreement on the key NM properties constituting the basis of the similarity assessment and the development of associated science-based and unequivocal rules. Currently, one of the most challenging NM properties to systematically assess in terms of similarity between two NMs is surface coating and functionalization, which lacks standardized parameters for description and characterization methodology. Standardization of characterization methods that lead to quantitative, unambiguous, and measurable parameters describing NM properties are necessary in order to build a sufficiently robust property-hazard database that allows for evidence-based refinement of our methodology, or any other attempt to systematically assess the similarity of NMs.

Structure activity relationship (SAR)-based read-across is an effective approach for addressing data gaps in human health risk assessment for 'data-poor' chemicals. In read-across, available data on chemical structural analogues are used to predict the toxicity potential of the data-poor chemical. This approach has long been recognized by regulatory agencies and used by industry to evaluate the hazards of chemicals for which there are limited direct data. Construction of a scientifically robust SAR-based read-across hazard assessment is a complex and iterative process involving multiple considerations in each step. Traditional in vivo data generated using regulatory guideline compliant study designs typically forms the basis for read-across assessments. Recently, however, new data streams have been explored and incorporated to enhance read-across predictivity. These in vitro and omics data streams may be used in different ways involving identification of hazards or to provide insight into modes of action for observed toxicological responses. These 'new approach methods' can also enable comparison of biological responses across analogues or a category of structurally related chemicals in order to establish a pattern of biological similarity in addition chemical similarity and/or to help address potency differences across a category. The purpose of this workshop session was to inform on practical considerations in conducting SAR-based read-across assessments and to review recent activities related to application of new approach methods to the practice of read-across., (© 2018 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Due to the exponential increase in the development and utilization of rare earth oxide nanoparticles (REO NPs) in various fields, the possibility of exposure in humans by inhalation has increased. However, there are little information about hazards of REO NPs and its mechanisms of toxicity. In this study, we evaluated the acute pulmonary inflammation using 10 REO NPs (Dy 2 O 3 , Er 2 O 3 , Eu 2 O 3 , Gd 2 O 3 La 2 O 3 , Nd 2 O 3 , Pr 6 O 11 , Sm 2 O 3 , Tb 4 O 7 , and Y 2 O 3 ) and four well-known toxic particles (CuO, NiO, ZnO, and DQ12). Minimum three doses per NP were instilled into the lungs of female Wistar rats at surface area dose metric and lung inflammation was evaluated at 24 h post-instillation by bronchoalveolar lavage fluid (BALF) analysis and histopathological observation. All types of REO NPs showed common pathological changes including mild to moderate infiltration of neutrophils and activated macrophages in the alveoli, peribronchial, and perivascular region. The inflammogenic potential evaluated by the number of granulocytes divided by the treated surface area dose showed all types of REO NPs has much higher inflammogenic potential than DQ12, ZnO, and NiO NPs. The correlation plot between the number of granulocytes and the potential for reactive oxygen species (ROS) generation showed a good correlation with exception of Pr 6 O 11 . The higher inflammogenic potential of REO NPs than that of well-known highly toxic particles imply that REO NPs need special attention for inhalation exposure and more studies are needed. In addition, the potential of ROS generation is one of the key factors producing lung inflammation by REO NPs.

Earlier we created a chemical hazard database via natural language processing of dossiers submitted to the European Chemical Agency with approximately 10 000 chemicals. We identified repeat OECD guideline tests to establish reproducibility of acute oral and dermal toxicity, eye and skin irritation, mutagenicity and skin sensitization. Based on 350-700+ chemicals each, the probability that an OECD guideline animal test would output the same result in a repeat test was 78%-96% (sensitivity 50%-87%). An expanded database with more than 866 000 chemical properties/hazards was used as training data and to model health hazards and chemical properties. The constructed models automate and extend the read-across method of chemical classification. The novel models called RASARs (read-across structure activity relationship) use binary fingerprints and Jaccard distance to define chemical similarity. A large chemical similarity adjacency matrix is constructed from this similarity metric and is used to derive feature vectors for supervised learning. We show results on 9 health hazards from 2 kinds of RASARs-"Simple" and "Data Fusion". The "Simple" RASAR seeks to duplicate the traditional read-across method, predicting hazard from chemical analogs with known hazard data. The "Data Fusion" RASAR extends this concept by creating large feature vectors from all available property data rather than only the modeled hazard. Simple RASAR models tested in cross-validation achieve 70%-80% balanced accuracies with constraints on tested compounds. Cross validation of data fusion RASARs show balanced accuracies in the 80%-95% range across 9 health hazards with no constraints on tested compounds.

Toxic and hazardous chemical species are ubiquitous, predominantly emitted by anthropogenic activities, and pose serious risks to human health and the environment. Thus, the sensing and subsequent capture of these chemicals, especially in the gas or vapor phase, are of extreme importance. To this end, metal-organic frameworks have attracted significant interest, as their high porosity and wide tunability make them ideal for both applications. These tailorable framework materials are particularly promising for the specific sensing and capture of targeted chemicals, as they can be designed to fit a diverse range of required conditions. This review will discuss the advantages of metal-organic frameworks in the sensing and capture of harmful gases and vapors, as well as principles and strategies guiding the design of these materials. Recent progress in the luminescent detection of aromatic and aliphatic volatile organic compounds, toxic gases, and chemical warfare agents will be summarized, and the adsorptive removal of fluorocarbons/chlorofluorocarbons, volatile radioactive species, toxic industrial gases and chemical warfare agents will be discussed.

It has been argued that the larger molecular weight of hazardous monoclonal antibodies may prevent their dermal absorption via occupational exposure. However, this assertion does not seem to be supported by direct evidence. Although the larger molecular weight may render monoclonal antibodies less probable to achieve therapeutic systemic level through dermal absorption, the concern in occupational health is whether these drugs can possibly attain a detectable level through repeated dermal exposure. Currently, there is no direct evidence to support a particular molecular weight above which a drug cannot achieve a detectable level following repeated occupational exposure. Therefore, the precautionary principle would dictate that repeated exposure of healthcare workers to hazardous monoclonal antibodies should be kept to a minimum.

For a tobacco heating product (THP), which heats rather than burns tobacco, the emissions of toxicants in the aerosol were compared with those in cigarette smoke under a machine-puffing regimen of puff volume 55 ml, puff duration 2 s and puff interval 30 s. The list of toxicants included those proposed by Health Canada, the World Health Organization Study Group on Tobacco Product Regulation (TobReg), the US Food and Drug Administration and possible thermal breakdown products. In comparison to the University of Kentucky 3R4F reference cigarette the toxicant levels in the THP1.0 emissions were significantly reduced across all chemical classes. For the nine toxicants proposed by TobReg for mandated reduction in cigarette emissions, the mean reductions in THP1.0 aerosol were 90.6-99.9% per consumable with an overall average reduction of 97.1%. For the abbreviated list of harmful and potentially harmful constituents of smoke specified by the US Food and Drug Administration Tobacco Products Scientific Advisory Committee for reporting in cigarette smoke (excluding nicotine), reductions in the aerosol of THP1.0 were 84.6-99.9% per consumable with an overall average reduction of 97.5%., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)

Consuming food contaminated by toxic elements (TEs) could pose a substantial risk to human health. Recently, biochar has been extensively studied as an effective soil ameliorant in situ because of its ability to suppress the phytoavailability of TEs. However, despite the research interest, the effects of biochar applications to soil on different TE concentrations in different plant parts remain unclear. Here, we synthesize 1813 individual observations data collected from 97 articles to evaluate the effects of biochar addition on TE concentrations in plant parts. We found that (1) the experiment type, biochar feedstock and pyrolysis temperature all significantly decreased the TE concentration in plant parts; (2) the responses of Cd and Pb concentrations in edible and indirectly edible plant parts were significantly more sensitive to the effect of biochar than the Zn, Ni, Mn, Cr, Co and Cu concentrations; and (3) the biochar dosage and surface area, significantly influenced certain TE concentrations in plant tissues as determined via correlation analysis. Moreover, the only exception in this study was found for metalloid element (i.e., As) concentrations in plants, which were not significantly influenced by biochar addition. Overall, the effects of biochar on TE concentrations in plant tissues were negative, at least on average, and the central trends suggest that biochar has a considerable ability to mitigate the transfer of TEs to food, thereby reducing the associated health risks. Our results provide an initial quantitative determination of the effects of biochar addition on multifarious TEs in different plant parts as well as an assessment of the ability of biochar to reduce TE concentrations in plants., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Hazard identification is the key step in risk assessment and management of manufactured nanomaterials (NM). However, the rapid commercialisation of nano-enabled products continues to out-pace the development of a prudent risk management mechanism that is widely accepted by the scientific community and enforced by regulators. However, a growing body of academic literature is developing promising quantitative methods. Two approaches have gained significant currency. Bayesian networks (BN) are a probabilistic, machine learning approach while the weight of evidence (WoE) statistical framework is based on expert elicitation. This comparative study investigates the efficacy of quantitative WoE and Bayesian methodologies in ranking the potential hazard of metal and metal-oxide NMs-TiO₂, Ag, and ZnO. This research finds that hazard ranking is consistent for both risk assessment approaches. The BN and WoE models both utilize physico-chemical, toxicological, and study type data to infer the hazard potential. The BN exhibits more stability when the models are perturbed with new data. The BN has the significant advantage of self-learning with new data; however, this assumes all input data is equally valid. This research finds that a combination of WoE that would rank input data along with the BN is the optimal hazard assessment framework.

The European Food Safety Authority (EFSA) is responsible for risk assessment of all aspects of food safety, including the establishment of procedures aimed at the identification of emerging risks to food safety. Here, a scoring system was developed for identifying chemicals registered under the European REACH Regulation that could be of potential concern in the food chain using the following parameters: (i) environmental release based on maximum aggregated tonnages and environmental release categories; (ii) biodegradation in the environment; (iii) bioaccumulation and in vivo and in vitro toxicity. The screening approach was tested on 100 data-rich chemicals registered under the REACH Regulation at aggregated volumes of at least 1000 tonnes per annum. The results show that substance-specific data generated under the REACH Regulation can be used to identify potential emerging risks in the food chain. After application of the screening procedure, priority chemicals can be identified as potentially emerging risk chemicals through the integration of exposure, environmental fate and toxicity. The default approach is to generate a single total score for each substance using a predefined weighting scenario. However, it is also possible to use a pivot table approach to combine the individual scores in different ways that reflect user-defined priorities, which enables a very flexible, iterative definition of screening criteria. Possible applications of the approaches are discussed using illustrative examples. Either approach can then be followed by in-depth evaluation of priority substances to ensure the identification of substances that present a real emerging chemical risk in the food chain.

The field of experimental toxicology is rapidly advancing by incorporating novel techniques and methods that provide a much more granular view into the mechanisms of potential adverse effects of chemical exposures on human health. The data from various in vitro assays and computational models are useful not only for increasing confidence in hazard and risk decisions, but also are enabling better, faster and cheaper assessment of a greater number of compounds, mixtures, and complex products. This is of special value to the field of green chemistry where design of new materials or alternative uses of existing ones is driven, at least in part, by considerations of safety. This article reviews the state of the science and decision-making in scenarios when little to no data may be available to draw conclusions about which choice in green chemistry is "safer." It is clear that there is no "one size fits all" solution and multiple data streams need to be weighed in making a decision. Moreover, the overall level of familiarity of the decision-makers and scientists alike with new assessment methodologies, their validity, value and limitations is evolving. Thus, while the "impact" of the new developments in toxicology on the field of green chemistry is great already, it is premature to conclude that the data from new assessment methodologies have been widely accepted yet., (© The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

In Switzerland, surface waters are protected by the Swiss Water Protection Ordinance (OEaux; OFEV 1998), which stipulates that the water quality shall be such that the water, suspended matter, and sediments contain no persistent synthetic substances to ensure the protection of aquatic life. Local agencies are in charge of water quality monitoring, using a set of validated methods. Several lists of priority substances have been developed for aquatic microcontaminants for surface water monitoring but not for sediments. Some local agencies have established sediment monitoring programs, but to date, there exists no harmonized methodology for sediment quality assessment in Switzerland. Within the main goal of developing and providing methodologies for monitoring sediment quality in Switzerland, a screening was performed to help prioritize sediment-relevant microcontaminants. The screening approach was largely based on the NORMAN (network of reference laboratories, research centers, and related organizations for monitoring emerging environmental substances) system and was carried out in four steps: (1) identification of candidate substances, (2) selection of sediment relevant substances, (3) classification of substances into different categories based on identified data gaps and envisaged actions, and (4) ranking within each action category. This paper describes the methodology used in the prioritization process for sediment-relevant substances and provides recommendations for monitoring strategies in Switzerland.

The leaching characteristics of hazardous materials from Ni-Cd batteries immersed in four typical water samples, i.e., water with NaCl, river water, tap water, and deionized water, were investigated to evaluate the potential environmental harm of spent Ni-Cd batteries in the water surroundings. It is shown that four water surroundings all could leach hazardous materials from the Ni-Cd batteries. The water with NaCl concentration of 66.7 mg L -1 had the highest leaching ability, the hazardous materials were leached after only approximately 50 days (average time, with a standard deviation of 4.1), while less than 100 days were needed in the others. An electrochemical corrosion is considered to be the main leaching mechanism leading to battery breakage, while the dissolution-deposition process and the powder route result in the leakage and transference of nickel and cadmium materials from the electrodes. The anions, i.e., SO 4 2- and Cl - , and dissolved oxygen in water were demonstrated to be the vital factors that influence the leaching processes. Thus, it is proposed that spent Ni-Cd batteries must be treated properly to avoid potential danger to the environment.

As ecotoxicologists we strive for a better understanding of how chemicals affect our environment. Humanity needs tools to identify those combinations of man-made chemicals and organisms most likely to cause problems. In other words: which of the millions of species are at risk from pollution? And which of the tens of thousands of chemicals contribute most to the risk? We identified our poor knowledge on physiological modes of action (how a chemical affects the energy allocation in an organism), and how they vary across species and toxicants, as a major knowledge gap. We also find that the key to predictive ecotoxicology is the systematic, rigorous characterization of physiological modes of action because that will enable more powerful in vitro to in vivo toxicity extrapolation and in silico ecotoxicology. In the near future, we expect a step change in our ability to study physiological modes of action by improved, and partially automated, experimental methods. Once we have populated the matrix of species and toxicants with sufficient physiological mode of action data we can look for patterns, and from those patterns infer general rules, theory and models.

The hazard of chemicals in the environment is inherently related to the molecular structure and derives simultaneously from various chemical properties/activities/reactivities. Models based on Quantitative Structure Activity Relationships (QSARs) are useful to screen, rank and prioritize chemicals that may have an adverse impact on humans and the environment. This paper reviews a selection of QSAR models (based on theoretical molecular descriptors) developed for cumulative multivariate endpoints, which were derived by mathematical combination of multiple effects and properties. The cumulative end-points provide an integrated holistic point of view to address environmentally relevant properties of chemicals.

REACH is a regulation of the European Union adopted to improve the safe use of chemicals with regard to human health and the environment. The safe use of chemicals can be achieved only if the hazard and the exposure of the substances are well characterized. Testing on animals has been traditionally the main tool for hazard assessment. For ethical and economic reasons, alternative ways of testing that do not use laboratory animals have been developed by different parties (regulatory agencies, researchers, industry) over the recent decades, and their proper use in hazard assessment is encouraged under REACH. In this chapter, we describe how (Q)SAR models and predictions are included into REACH and their adequate use promoted by the European Chemicals Agency (ECHA).

Recent advances in the field of continuous flow chemistry allow the multistep preparation of complex molecules such as APIs (Active Pharmaceutical Ingredients) in a telescoped manner. Numerous examples of laboratory-scale applications are described, which are pointing towards novel manufacturing processes of pharmaceutical compounds, in accordance with recent regulatory, economical and quality guidances. The chemical and technical knowledge gained during these studies is considerable; nevertheless, connecting several individual chemical transformations and the attached analytics and purification holds hidden traps. In this review, we summarize innovative solutions for these challenges, in order to benefit chemists aiming to exploit flow chemistry systems for the synthesis of biologically active molecules., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

A continuous flow process is presented that enables the efficient synthesis and derivatization of 1,2,4-thiadiazole heterocycles. Special attention was given to the safe handling of the versatile yet hazardous trichloromethane sulfenylchloride reagent including its in-line quenching in order to eliminate malodourous and corrosive by-products. Based on this flow method gram quantities of 5-chloro-3-phenyl-1,2,4-thiadiazole were safely prepared allowing for further elaboration of this valuable building block by reaction with different nitrogen-, sulfur- and oxygen-based nucleophiles. This synthetic approach was subsequently applied to generate a series of bromophenyl-5-chloro-1,2,4-thiadiazoles providing a valuable entry towards further structural diversification on this important heterocyclic scaffold., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Generation and reactions of methyl azide (MeN 3 ) were successfully performed by using a flow reactor system, demonstrating that the flow method serves as a safe method for handling hazardous explosive methyl azide. The reaction of NaN 3 and Me 2 SO 4 in a flow reactor gave a MeN 3 solution, which was used for Huisgen reaction with benzoyl cyanide in a flow reactor after minimal washing. The resulting 1-methyl-5-benzoyltetrazole serves as a key intermediate of picarbutrazox (IX), a new potent pesticide., (Copyright © 2017. Published by Elsevier Ltd.)

The knowledge of radioactivity content in various radionuclides in building materials plays an important role in health physics; therefore, we measured the amount of naturally occurring radionuclides in building material (sand, granite, marble, and limestone) samples of different grain sizes by using NaI (Tl) and MCA1024 gamma-ray spectrometers. Data analyses were performed to determine 226 Ra, 232 Th, and 4 °K activity concentrations. The results revealed an inverse relationship between activity concentration and grain size of the samples. The radium equivalent activity (Ra eq ), representative level index I, and annual absorbed dose rate were calculated., (Copyright © 2017. Published by Elsevier Ltd.)

In this study, we systematically investigated the effect of multiwall carbon nanotubes (MWCNTs) on the removal of tetrabromobisphenol A (TBBPA) mediated by horseradish peroxidase (HRP) at varying important conditions. The results suggested that the presence of MWCNTs significantly enhanced the removal of TBBPA mediated by HRP and the reaction rate constant was linear with the MWCNTs dosage. The enhancement of MWCNTs on the HRP-mediated reaction was attributed to two facts, one is that MWCNTs protected HRP from inactivation, the other is that the presence of MWCNTs made the homogeneous reaction of TBBPA be heterogeneous reaction by adsorbing TBBPA on its surface. Moreover, the influence of MWCNTs on TBBPA products distribution was further elucidated. We found that the species of reaction product had no difference between the HRP-mediated systems with and without the presence of MWCNTs. However, the presence of MWCNTs significantly decreased the yields of each product. These results give insight into the role of MWCNTs in HRP-mediated TBBPA reactions and provide theoretical foundation for potential development of novel enzymatic methods to control TBBPA contamination. MWCNTs enhanced the removal of TBBPA mediated by HRP/H 2 O 2 , because it protected HRP from inactivation and adsorbed TBBPA on its surface to form a heterogeneous reaction process., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Previously, a calcium montmorillonite clay (NovaSil) included in the diet of animals has been shown to bind aflatoxin B1 (AfB1) and reduce the symptoms of aflatoxicosis. To investigate and improve the capacity and efficacy of clay-based materials as aflatoxin sorbents, we developed and tested calcium and sodium montmorillonite clays amended with nutrients including l-carnitine and choline. Also, we determined the sorption of AfB1 by isothermal analysis and tested the ability of these amended sorbents to protect adult hydra from AfB1 toxicity. The results showed that exchanging montmorillonite clays with l-carnitine and choline inhibited swelling of the clays and increased the sorption capacity and efficacy of clay surfaces for AfB1. Results from dehydroxylated and heat-collapsed clays suggested that AfB1 was primarily adsorbed in the clay interlayer, as predicted from thermodynamic calculations and computational modeling. The hydra bioassay further indicated that the modified clays can significantly protect adult hydra from AfB1 with as low as 0.005% clay inclusion. This enterosorbent therapy may also be applied to screen hazardous chemicals such as pesticides and PAHs based on similar sorption mechanisms. Taken together, enterosorbent therapy could be delivered in nutritional supplements, foods that are vulnerable to aflatoxin contamination, flavored liquids and animal feeds during emergencies and outbreaks of acute aflatoxicosis, and as a screening model for hazardous environmental chemicals.

Proteomics studies of fungal systems have progressed dramatically based on the availability of more fungal genome sequences in recent years. Different proteomics strategies have been applied toward characterization of fungal proteome and revealed important gene functions and proteome dynamics. Presented here is the application of shot-gun proteomic technology to study the bio-remediation of environmental hazards by white-rot fungus. Lignin, a naturally abundant component of the plant biomass, is discovered to promote the degradation of Azo dye by white-rot fungus Irpex lacteus CD2 in the lignin/dye/fungus system. Shotgun proteomics technique was used to understand degradation mechanism at the protein level for the lignin/dye/fungus system. Our proteomics study can identify about two thousand proteins (one third of the predicted white-rot fungal proteome) in a single experiment, as one of the most powerful proteomics platforms to study the fungal system to date. The study shows a significant enrichment of oxidoreduction functional category under the dye/lignin combined treatment. An in vitro validation is performed and supports our hypothesis that the synergy of Fenton reaction and manganese peroxidase might play an important role in DR5B dye degradation. The results could guide the development of effective bioremediation strategies and efficient lignocellulosic biomass conversion.

We developed a lead substances selection approach based on the concept of mixture classification of UN GHS for the purpose of efficient risk assessment of mixtures consisting of multiple components. Lead substances selection methods are being actively developed in Europe, but these methods are predicated on the regulations and information sources available within Europe and are therefore not readily applicable to countries outside Europe. In this study, the features of the GHS-based approach and the risk assessment results for outdoor painting work as a specific utilization example of the GHS-based approach were described. Comparison with the DPD + method and the CCA method proposed in Europe revealed that the GHS-based approach resulted in the selection of the safest lead substances. The GHS method, like the DPD + method, is a classification-based approach. We believe that a classification-based approach based on the GHS method can be an appropriate tool to efficiently implement risk assessment of mixtures for countries outside Europe. Some tools for business operators to conduct the management of chemicals using the GHS classification have been established in Japan. We plan to propose the GHS-based approach as a standardized assessment tool., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Engineered nanomaterials (ENMs) are being produced for an increasing number of applications. Therefore, it is important to assess and categorize ENMs on the basis of their hazard potential. The immune system is the foremost defence against foreign bodies. Here we performed cytokine profiling of a panel of nineteen representative ENMs procured from the Joint Research Centre (JRC) and commercial sources. Physicochemical characterization was performed using dynamic light scattering. The ENMs were all shown to be endotoxin content free. The human macrophage-differentiated THP.1 cell line was employed for cytotoxicity screening and based on the calculated IC 50 values, the multi-walled carbon nanotubes (MWCNTs), ZnO, Ag and SiO 2 NMs were found to be the most cytotoxic while single-walled carbon nanotubes (SWCNTs), TiO 2 , BaSO 4 and CeO 2 NMs, as well as the nanocellulose materials, were non-cytotoxic (at doses up to 100 µg/mL). Multiplex profiling of cytokine and chemokine secretion indicated that the TiO 2 , SiO 2 , BaSO 4 , CeO 2 and nanocellulose materials induced potent inflammatory responses at sub-cytotoxic doses. Hierarchical clustering of cytokine responses coupled with pathway analysis demonstrated that the panel of ENMs could be segregated into two distinct groups characterized by activation and deactivation, respectively, of PPAR (peroxisome proliferator-activated receptor)/LXR (liver X receptor/retinoid X receptor) nuclear receptor pathways (NRPs). Furthermore, using rosiglitazone, a selective PPAR-γ agonist, we could show that PPAR-γ played an important role in the activation of inflammatory responses in cells exposed to TiO 2 and SiO 2 NMs. These studies show that ENMs of diverse chemical compositions can be grouped according to their inflammatory potential.

Mechanochemical dechlorination and destruction of polychlorinated dibenzo-p-dioxins and -furans (PCDD/F) on fly ash from Municipal Solid Waste Incineration was tested with and without additives (CaO and CaO/aluminium powder). The first results disappointed because of obvious PCDD/F-reformation and a second test series was conducted after removing soluble salts (NaCl, KCl …) by thorough two-stage water washing. This second test series was successful and demonstrated good destruction results, especially with combined CaO/aluminium powder as additive. In a third test series salt was again added to the water-washed fly ash, and the first, poor results were largely reconstituted. For all tests a fairly complete (94 out of 136 congeners) isomer-specific analysis was conducted and analysed, allowing to differentiate between, e.g., 2,3,7,8-substituted PCDD/F and congeners formed following the chlorophenol route. The first became more important in the samples series Fly Ash, Milled Fly Ash, milling with added CaO, and milling with CaO/aluminium-addition. The second follow the opposite trend. This isomer-specific analysis will form the basis for further study using Principal Component Analysis., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Natural products are becoming increasingly popular in multiple fields involving medicines, foods and beverages. However, due to the frequent occurrence of poisoning incidents, their toxicity and safety have caused a serious concern. Here we report a method of biosensor-based two-phase pharmacological profiling (BTPP) for discovery, monitor and control of receptor-targeted natural products. BTPP uses a resonant waveguide grating biosensor for label-free and non-invasive detection of intracellular dynamic mass redistribution (DMR), a phenomenon caused by protein relocalization after receptors receiving stimulation from toxicants. The method can not only facilitate the identification of hazardous materials but also quantify their bioactivity by EC 50 . As a proof of concept, the method was successfully applied to recognize Daturae Flos (DF), an herb that can antagonize muscarinic acetylcholine M 2 receptor and further cause poisoning, from other easily confused species. BTPP combined with high performance liquid chromatography revealed that scopolamine and hyoscyamine in DF were the key marker compounds. Moreover, the method accurately picked out 2 M 2 receptor antagonists from 25 natural compounds, displaying its potential in high-throughput screening. This study provides a systematic illustration about the establishment, applicability and advantages of BTPP, which contributes to the safety assessment of natural products in related fields., (Copyright © 2017 Elsevier B.V. All rights reserved.)

In Europe, REACH legislation encourages the use of alternative in silico methods such as (Q)SAR models. According to the recent progress of Chemical Substances Control Law (CSCL) in Japan, (Q)SAR predictions are also utilized as supporting evidence for the assessment of bioaccumulation potential of chemicals along with read across. Currently, the effective use of read across and QSARs is examined for other hazards, including biodegradability. This paper describes the results of external validation and improvement of CATALOGIC 301C model based on more than 1000 tested new chemical substances of the publication schedule under CSCL. CATALOGIC 301C model meets all REACH requirements to be used for biodegradability assessment. The model formalism built on scientific understanding for the microbial degradation of chemicals has a well-defined and transparent applicability domain. The model predictions are adequate for the evaluation of the ready degradability of chemicals.

Numerous studies have been published in the past years investigating the transcriptome of the zebrafish embryo (ZFE) upon being subjected to chemical stress. Aiming at a more mechanistic understanding of the results of such studies, knowledge about commonalities of transcript regulation in response to chemical stress is needed. Thus, our goal in this study was to identify and interpret genes and gene sets constituting a general response to chemical exposure. Therefore, we aggregated and reanalyzed published toxicogenomics data obtained with the ZFE. We found that overlap of differentially transcribed genes in response to chemical stress across independent studies is generally low and the most commonly differentially transcribed genes appear in less than 50% of all treatments across studies. However, effect size analysis revealed several genes showing a common trend of differential expression, among which genes related to calcium homeostasis emerged as key, especially in exposure settings up to 24 h post-fertilization. Additionally, we found that these and other downregulated genes are often linked to anatomical regions developing during the respective exposure period. Genes showing a trend of increased expression were, among others, linked to signaling pathways (e.g., Wnt, Fgf) as well as lysosomal structures and apoptosis. The findings of this study help to increase the understanding of chemical stress responses in the developing zebrafish embryo and provide a starting point to improve experimental designs for this model system. In future, improved time- and concentration-resolved experiments should offer better understanding of stress response patterns and access to mechanistic information., (© The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology.)

Sustainable molecular design of less hazardous chemicals presents a potentially transformative approach to protect public health and the environment. Relationships between molecular descriptors and toxicity thresholds previously identified the octanol-water distribution coefficient, log D, and the HOMO-LUMO energy gap, ΔE, as two useful properties in the identification of reduced aquatic toxicity. To determine whether these two property-based guidelines are applicable to sublethal oxidative stress (OS) responses, two common aquatic in vivo models, the fathead minnow (Pimephales promelas) and zebrafish (Danio rerio), were employed to examine traditional biochemical biomarkers (lipid peroxidation, DNA damage, and total glutathione) and antioxidant gene activation following exposure to eight structurally diverse industrial chemicals (bisphenol A, cumene hydroperoxide, dinoseb, hydroquinone, indene, perfluorooctanoic acid, R-(-)-carvone, and tert-butyl hydroperoxide). Bisphenol A, cumene hydroperoxide, dinoseb, and hydroquinone were consistent inducers of OS. Glutathione was the most consistently affected biomarker, suggesting its utility as a sensitivity response to support the design of less hazardous chemicals. Antioxidant gene expression (changes in nrf2, gclc, gst, and sod) was most significantly (p < 0.05) altered by R-(-)-carvone, cumene hydroperoxide, and bisphenol A. Results from the present study indicate that metabolism of parent chemicals and the role of their metabolites in molecular initiating events should be considered during the design of less hazardous chemicals. Current empirical and computational findings identify the need for future derivation of sustainable molecular design guidelines for electrophilic reactive chemicals (e.g., SN2 nucleophilic substitution and Michael addition reactivity) to reduce OS related adverse outcomes in vivo.

The current state of the art of (Quantitative) Structure-Activity Relationships ((Q)SARs) to predict environmental toxicity is assessed along with recommendations to develop these models further. The acute toxicity of compounds acting by the non-polar narcotic mechanism of action can be well predicted, however other approaches, including read-across, may be required for compounds acting by specific mechanisms of action. The chronic toxicity of compounds to environmental species is more difficult to predict from (Q)SARs, with robust data sets and more mechanistic information required. In addition, the toxicity of mixtures is little addressed by (Q)SAR approaches. Developments in environmental toxicology including Adverse Outcome Pathways (AOPs) and omics responses should be utilised to develop better, more mechanistically relevant, (Q)SAR models.

The Microtox assay, a bioluminescence inhibition assay with the marine bacterium Aliivibrio fischeri, is one of the most popular bioassays for assessing the cytotoxicity of organic chemicals, mixtures and environmental samples. Most environmental chemicals act as baseline toxicants in this short-term screening assay, which is typically run with only 30 min of exposure duration. Numerous Quantitative Structure-Activity Relationships (QSARs) exist for the Microtox assay for nonpolar and polar narcosis. However, typical water pollutants, which have highly diverse structures covering a wide range of hydrophobicity and speciation from neutral to anionic and cationic, are often outside the applicability domain of these QSARs. To include all types of environmentally relevant organic pollutants we developed a general baseline toxicity QSAR using liposome-water distribution ratios as descriptors. Previous limitations in availability of experimental liposome-water partition constants were overcome by reliable prediction models based on polyparameter linear free energy relationships for neutral chemicals and the COSMOmic model for charged chemicals. With this QSAR and targeted mixture experiments we could demonstrate that ionisable chemicals fall in the applicability domain. Most investigated water pollutants acted as baseline toxicants in this bioassay, with the few outliers identified as uncouplers or reactive toxicants. The main limitation of the Microtox assay is that chemicals with a high melting point and/or high hydrophobicity were outside of the applicability domain because of their low water solubility. We quantitatively derived a solubility cut-off but also demonstrated with mixture experiments that chemicals inactive on their own can contribute to mixture toxicity, which is highly relevant for complex environmental mixtures, where these chemicals may be present at concentrations below the solubility cut-off.

Chemical property estimation is a key component in many industrial, academic, and regulatory activities, including in the risk assessment associated with the approximately 1000 new chemical pre-manufacture notices the United States Environmental Protection Agency (US EPA) receives annually. The US EPA evaluates fate, exposure and toxicity under the 1976 Toxic Substances Control Act (amended by the 2016 Frank R. Lautenberg Chemical Safety for the 21 st Century Act), which does not require test data with new chemical applications. Though the submission of data is not required, the US EPA has, over the past 40 years, occasionally received chemical-specific data with pre-manufacture notices. The US EPA has been actively using this and publicly available data to develop and refine predictive computerized models, most of which are housed in EPI Suite™, to estimate chemical properties used in the risk assessment of new chemicals. The US EPA develops and uses models based on (quantitative) structure-activity relationships ([Q]SARs) to estimate critical parameters. As in any evolving field, (Q)SARs have experienced successes, suffered failures, and responded to emerging trends. Correlations of a chemical structure with its properties or biological activity were first demonstrated in the late 19 th century and today have been encapsulated in a myriad of quantitative and qualitative SARs. The development and proliferation of the personal computer in the late 20 th century gave rise to a quickly increasing number of property estimation models, and continually improved computing power and connectivity among researchers via the internet are enabling the development of increasingly complex models.