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Hazard and risk assessment of complex petroleum-derived substances has been in a state of continuous improvement since the 1970s, with the development of approaches that continue to be applied and refined. Alternative feeds are defined here as those coming into a refinery or chemical plant that are not hydrocarbons from oil and gas extraction such as biologically derived oils, pyrolysis oil from biomass or other, and recycled materials. These feeds are increasingly being used for production of liquid hydrocarbon streams, and hence, there is a need to assess these alternatives, subsequent manufacturing and refining processes and end products for potential risk to humans and the environment. Here we propose a tiered, problem formulation-driven framework for assessing the safety of hydrocarbon streams and products derived from alternative feedstocks in use. The scope of this work is only focused on petrochemical safety assessment, though the principles may be applicable to other chemistries. The framework integrates combinations of analytical chemistry, in silico and in vitro tools, and targeted testing together with conservative assumptions/approaches to leverage existing health, environmental, and exposure data, where applicable. The framework enables the identification of scenarios where de novo hazard and/or exposure assessments may be needed and incorporates tiered approaches to do so. It can be applied to enable decisions efficiently and transparently and can encompass a wide range of compositional space in both feedstocks and finished products, with the objective of ensuring safety in manufacturing and use. [ABSTRACT FROM AUTHOR]

Introduction: Many secondary metabolites isolated from plants have been described in the literature owing to their important biological properties and possible pharmacological applications. However, the identification of compounds present in complex plant extracts has remained a great scientific challenge, is often laborious, and requires a long research time with high financial cost. Objectives: The aim of this study was to develop a method that allows the identification of secondary metabolites in plant extracts with a high degree of confidence in a short period of time. Material and methods: In this study, an ethanolic extract of Coffea arabica leaves was used to validate the proposed method. Countercurrent chromatography was chosen as the initial step for extraction fractionation using gradient elution. Resulting fractions presented a variation of compounds concentrations, allowing for statistical total correlation spectroscopy (STOCSY) calculations between liquid chromatography coupled with high‐resolution tandem mass spectrometry (LC‐HRMS/MS) and NMR across fractions. Results: The proposed method allowed the identification of 57 compounds. Of the annotated compounds, 20 were previously described in the literature for the species and 37 were reported for the first time. Among the inedited compounds, we identified flavonoids, alkaloids, phenolic acids, coumarins, and terpenes. Conclusion: The proposed method presents itself as a valid alternative for the study of complex extracts in an effective, fast, and reliable way that can be reproduced in the study of other extracts. A novel method was developed to identify secondary metabolites in plant extracts with high confidence and efficiency. Using an ethanolic extract of Coffea arabica leaves, countercurrent chromatography was employed for extraction fractionation, followed by statistical total correlation spectroscopy (STOCSY) calculations between liquid chromatography coupled with high‐resolution tandem mass spectrometry (LC‐HRMS/MS) and NMR. This approach successfully identified 57 compounds, with 20 known and 37 newly reported compounds, including flavonoids, alkaloids, phenolic acids, coumarins, and terpenes. [ABSTRACT FROM AUTHOR]

Fluoroarenes are widely used in medicinal, agricultural, and materials chemistry, and yet their production remains a critical challenge in organic synthesis. Indeed, the nearly identical physical properties of these vital building blocks hinders their purification by traditional methods, such as flash chromatography or distillation. As a result, the Balz-Schiemann reaction is currently employed to prepare fluoroarenes instead of more atom-economical C-H fluorination reactions, which produce inseparable mixtures of regioisomers. Herein, we propose an alternative solution to this problem: the purification of mixtures of fluoroarenes using metal-organic frameworks (MOFs). Specifically, we demonstrate that controlling the interaction of fluoroarenes with adjacent coordinatively unsaturated Mg2+ centers within a MOF enables the separation of fluoroarene mixtures with unparalleled selectivities. Liquid-phase multicomponent equilibrium adsorption data and breakthrough measurements coupled with van der Waals-corrected density functional theory calculations reveal that the materials Mg2(dobdc) (dobdc4- = 2,5-dioxidobenzene-1,4-dicarboxylate) and Mg2(m-dobdc) (m-dobdc4- = 2,4-dioxidobenzene-1,5-dicarboxylate) are capable of separating the difluorobenzene isomers from one another. Additionally, these frameworks facilitate the separations of fluoroanisoles, fluorotoluenes, and fluorochlorobenzenes. In addition to enabling currently unfeasible separations for the production of fluoroarenes, our results suggest that carefully controlling the interaction of isomers with not one but two strong binding sites within a MOF provides a general strategy for achieving challenging liquid-phase separations.

Biohybrids composed of microorganisms and nanoparticles have emerged as potential systems for bioenergy and high-value compound production from CO2 and light energy, yet the cellular and metabolic processes within the biological component of this system are still elusive. Here we dissect the biohybrid composed of the anaerobic acetogenic bacterium Moorella thermoacetica and cadmium sulphide nanoparticles (CdS) in terms of physiology, metabolism, enzymatics and transcriptomic profiling. Our analyses show that while the organism does not grow on L-cysteine, it is metabolized to acetate in the biohybrid system and this metabolism is independent of CdS or light. CdS cells have higher metabolic activity, despite an inhibitory effect of Cd2+ on key enzymes, because of an intracellular storage compound linked to arginine metabolism. We identify different routes how cysteine and its oxidized form can be innately metabolized by the model acetogen and what intracellular mechanisms are triggered by cysteine, cadmium or blue light.

BackgroundAmbient environmental pollutants have been shown to adversely affect respiratory health in susceptible populations. However, the role of simultaneous exposure to multiple diverse environmental pollutants is poorly understood.ObjectiveWe applied a multidomain, multipollutant approach to assess the association between pediatric lung function measures and selected ambient air pollutants and pesticides.MethodsUsing data from the US EPA and California Pesticide Use Registry, we reconstructed three months prior exposure to ambient air pollutants ((ozone (O3), nitrogen dioxide (NO2), particulate matter with a median aerodynamic diameter

The presence of liquid water makes our planet habitable. Water in soils, sediments, lakes, rivers and the ocean forms the largest habitat for life on Earth. During life and upon death, all organisms release dissolved organic matter (DOM) to their environment. These molecular traces of life travel with water through land- and seascapes. DOM in the ocean and freshwaters contains more carbon than all living biomass on Earth combined. An in-depth knowledge of the molecular composition of the DOM pool is crucial to understand its role in the global carbon cycle. DOM is one of the most diverse mixtures known. So far, only the structure of a few components has been elucidated, thus, its molecular composition remains largely unknown. NMR spectroscopy is a promising tool for the molecular-level characterization of complex mixtures such as DOM. Major drawbacks of this spectroscopic technique in the past were the lack of sensitivity and insufficient spectral resolution. Large amounts of DOM were required and overlapping signals of the manifold DOM constituents resulted in broad unresolved spectral features. Recent technical and methodical improvements, the application of multivariate statistical analyses and the development of new chemical derivatization strategies may overcome these limitations. Here, we review the application of NMR spectroscopy within the quickly emerging field of the structural characterization of marine DOM. In the first section, this review covers fundamental aspects of NMR spectroscopy and its application to the analysis of DOM. The major points in the following are (1) a comprehensive overview of the current state of NMR spectroscopy for the analysis of marine DOM, (2) a discussion of the most important technical and methodical improvements and (3) suggestions for future implementations of NMR for the characterization of DOM. This review provides an overview for experts but also serves as a starting point for beginners. [ABSTRACT FROM AUTHOR]

Platelet‐rich plasma (PRP) has become an accepted and general wound healing approach with an extremely wide range of applications. Despite considerable diversity in the composition of platelet‐rich plasma products that are applied in specific wound healing usage, it is widely recognised that such diverse platelet‐rich plasma complex mixtures routinely display hormetic‐like biphasic concentrations that are independent of the tissue treated and endpoints measured. The present paper is the first to place the area of platelet‐rich plasma‐biomedical research and applications within an hormetic framework. The platelet‐rich plasma area is also unique as it represents the application of the hormetic concept to the issue of complex biological mixtures. [ABSTRACT FROM AUTHOR]

Gas-phase trace chemical detection techniques such as ion mobility spectrometry (IMS) and differential mobility spectrometry (DMS) can be used in many settings, such as evaluating the health condition of patients or detecting explosives at airports. These devices separate chemical compounds in a mixture and provide information to identify specific chemical species of interest. Further, these types of devices operate well in both controlled lab environments and in-field applications. Frequently, the commercial versions of these devices are highly tailored for niche applications (e.g., explosives detection) because of the difficulty involved in reconfiguring instrumentation hardware and data analysis software algorithms. In order for researchers to quickly adapt these tools for new purposes and broader panels of chemical targets, it is critical to develop new algorithms and methods for generating libraries of these sensor responses. Microelectromechanical system (MEMS) technology has been used to fabricate DMS devices that miniaturize the platforms for easier deployment; however, concurrent advances in advanced data analytics are lagging. DMS generates complex three-dimensional dispersion plots for both positive and negative ions in a mixture. Although simple spectra of single chemicals are straightforward to interpret (both visually and via algorithms), it is exceedingly challenging to interpret dispersion plots from complex mixtures with many chemical constituents. This study uses image processing and computer vision steps to automatically identify features from DMS dispersion plots. We used the bag-of-words approach adapted from natural language processing and information retrieval to cluster and organize these features. Finally, a support vector machine (SVM) learning algorithm was trained using these features in order to detect and classify specific compounds in these represented conceptualized data outputs. Using this approach, we successfully maintain a high level of correct chemical identification, even when a gas mixture increases in complexity with interfering chemicals present.

Chronic liver diseases affect more than 1 billion people worldwide and represent one of the main public health issues. Nonalcoholic fatty liver disease (NAFLD) accounts for the majority of mortal cases, while there is no currently approved therapeutics for its treatment. One of the prospective approaches to NAFLD therapy is to use a mixture of natural compounds. They showed effectiveness in alleviating NAFLD-related conditions including steatosis, fibrosis, etc. However, understanding the mechanism of action of such mixtures is important for their rational application. In this work, we propose a new dereplication workflow for deciphering the mechanism of action of the lignin-derived natural compound mixture. The workflow combines the analysis of molecular components with high-resolution mass spectrometry, selective chemical tagging and deuterium labeling, liver tissue penetration examination, assessment of biological activity in vitro, and computational chemistry tools used to generate putative structural candidates. Molecular docking was used to propose the potential mechanism of action of these structures, which was assessed by a proteomic experiment. [ABSTRACT FROM AUTHOR]

Substances of unknown or variable composition, complex reaction products, and biological materials (UVCBs) pose a unique challenge to regulators and to product registrants, who are required to characterize their fate, exposure, hazard, and potential risks to human health and the environment. To address these challenges and ensure an efficient and fit‐for‐purpose process, it is proposed that the ecological risks of UVCBs be assessed following a tiered strategy. The development of this approach required exploring how substance composition ties into hazard and exposure information and determining the extent to which a UVCB needs to be characterized to ensure a robust risk assessment. The present study highlights the key aspects of this new method. It presents how a tiered substance characterization approach can be integrated into broader UVCB risk‐assessment schemes to encourage an examination of data needs before a full substance characterization is performed. The first tier of the characterization process, Tier 0, is a fundamental step that includes data from basic, lower‐resolution compositional analyses. Tier 0 assessments can be used to inform hazard and exposure for any substance of interest. The need for more sophisticated, higher‐tier characterization is determined by the level of uncertainty of the risk assessment. The next step will integrate a tiered exposure assessment into the characterization scheme featured in the present study, to create a more complete risk‐assessment framework. Environ Toxicol Chem 2022;41:2649–2657. © 2022 Her Majesty the Queen in Right of Canada, Health and Environmental Sciences Institute and The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC. Reproduced with the permission of the Minister of Environment and Climate Change Canada. [ABSTRACT FROM AUTHOR]

New psychoactive substance (NPS) misuse represents a critical social and health problem. Herein, a novel flipped approach is presented for the detection of psychoactive substances in complex mixtures using portable Raman spectroscopy. This consists firstly of evaluating the spectral dissimilarities of an NPS product to its constituent adulterants followed by detection of the NPS by means of key spectral signatures. To demonstrate it, three structurally diverse NPS and four commonly used adulterants were selected. A Design‐of‐Experiments guided approach was employed to determine the composition of simulate street samples, ranging from binary to quinary mixtures of varying concentrations. Spectra were acquired for all mixtures using a portable Raman spectrometer and examined using projection analysis on model systems, developed via principal component analysis using reference materials. For all 21 mixtures investigated, the innovative 'flipped' methodology resulted in isolated and unequivocal detection of the NPS. Interestingly, the NPS signatures were consistent across all mixtures investigated and were 1712, 1000, and 777/1022 cm−1 for 5F‐PB‐22, phenibut, and N‐Me‐2‐AI containing samples, respectively. Thus indicating that the developed model systems could be applicable to structural analogs. NPS were detected to concentrations as low as 6.0% w/w. This flipped methodology was benchmarked to the instrument's output algorithms and outperformed these in terms of NPS detection, particularly for low concentration ternary and quinary mixtures. As a result, this study represents a critical change in the conceptualization of novel approaches for the detection of psychoactive substances and further denotes a blueprint for the development of detection methodologies of target analytes in complex mixtures. [ABSTRACT FROM AUTHOR]

Areas Covered: This paper outlines the selection of NAMs, including in vitro assays using primary rat cortical neurons, zebrafish embryos, and Caenorhabditis elegans . These assays aim to assess neurotoxic endpoints such as neuronal activity and behavioral responses. Microelectrode array recordings of rat cortical neurons provide insights into the impact of botanical extracts on neuronal function, while the zebrafish embryos and C. elegans assays evaluate neurobehavioral responses. The paper also provides an account of the selection of botanical case studies based on expert judgment and existing neuroactivity/toxicity information. The proposed battery of assays will be tested with these case studies to evaluate their utility for neurotoxicity screening., Expert Opinion: The complexity of botanicals necessitates the use of multiple NAMs for effective neurotoxicity screening. This paper discusses the evaluation of methodologies to develop a robust framework for evaluating botanical safety, including complex neuronal models and key neurodevelopmental process assays. It aims to establish a comprehensive screening framework.

Background: Gemcitabine is the first-line chemotherapy drug that can easily cause chemotherapy resistance. Huaier is a traditional Chinese medicine and shows an antitumor effect in pancreatic cancer, but whether it can enhance the gemcitabine chemotherapeutic response and the potential mechanism remain unknown., Purpose: This study was performed to explore the effect of Huaier in promoting the tumor-killing effect of gemcitabine and elucidate the possible mechanism in pancreatic cancer., Methods: Cell Counting Kit-8 assays and colony formation assays were used to detect proliferation after different treatments. Protein coimmunoprecipitation was applied to demonstrate protein interactions. Nuclear protein extraction and immunofluorescence were used to confirm the intracellular localization of the proteins. Western blotting was performed to detect cell proliferation-related protein expression or cancer stem cell-associated protein expression. Sphere formation assays and flow cytometry were used to assess the stemness of pancreatic cancer cells. The in vivo xenograft model was used to confirm the inhibitory effect under physiological conditions, and immunohistochemistry was used to detect protein expression., Results: Huaier suppressed the proliferation and stem cell-like properties of pancreatic cancer cells. We found that Huaier suppressed the expression of forkhead box protein M1 (FoxM1). In addition, Huaier inhibited FoxM1 function by blocking its nuclear translocation. Treatment with Huaier reversed the stemness induced by gemcitabine in a FoxM1-dependent manner. Furthermore, we verified the above results by an in vivo study, which reached the same conclusion as those in vitro., Conclusion: Overall, this study illustrates that Huaier augments the tumor-killing effect of gemcitabine through suppressing the stemness induced by gemcitabine in a FoxM1-dependent way. These results indicate that Huaier can be applied to overcome gemcitabine resistance., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Biothiols are important for numerous cellular processes, such as resisting oxidative stress and protecting cell health. Their abnormal levels and molecular configurations have been associated with various diseases. So, establishing an effective and reliable method for the specific detection and enantiomeric discrimination of diverse biothiols is highly meaningful. We have developed a new NMR and CD probe using 1,4-dinitroimidazole, specifically targeting the thiol group. This probe allows for the specific detection and enantiomeric recognition of biothiols in complex mixtures. We achieved this by identifying the distinguishable 1H NMR signals of 2nd in imidazole-ring of the resulting 4NI-biothiols in the downfield region at 7–8 ppm and newly discovered induced CD signals within 290-430 nm. Using this probe, the limits of detection of Cys, GSH, and Hcy, the recovery rates, and the concentration of GSH extracted from HEK293T cells were determined by measuring the unique downfield 1H NMR signals. Moreover, Cys, GSH, and Hcy can be discriminated simultaneously in complicated samples at a pH range of 2–3.5. Furthermore, this probe can also be utilized to sense chiral thiol-drugs. This method offers a cost-effective and accurate sensing solution for the specific detection of biothiols in complex mixtures, with stereochemical recognition. [Display omitted] • 1,4-DNI, as an NMR and CD probe, was utilized for specific labelling biothiols in an aqueous solution. • 4NI-bothiols showed the distinctive 1H NMR signals in the downfield region. • 4NI-bothiols generated additional ICD signals between 290 and 430 nm. • Biothiols can be simultaneously analyzed at pH 2∼3.5 and quantified in a mixture without a linear curve. [ABSTRACT FROM AUTHOR]

The ability to perform in vitro splicing assays has paved the way for in-depth studies of the mechanisms and machinery involved in the process of splicing. The in vitro splicing assay is a valuable experimental approach that combines the complexity of the spliceosome and regulatory systems with the flexibility of performing endless splicing and alternative splicing reactions. Through the use of crude nuclear extract and radiolabeled pre-mRNA, spliced mRNAs can be visualized using autoradiography for downstream analysis. This chapter describes the necessary steps to perform an in vitro splicing reaction, including the generation of the key components necessary for the splicing reaction; nuclear extract.

Abstract The experimental values of skin permeability coefficients, required for dermal exposure assessment, are not readily available for many chemicals. The existing estimation approaches are either less accurate or require many parameters that are not readily available. Furthermore, current estimation methods are not easy to apply to complex environmental mixtures. We present two models to estimate the skin permeability coefficients of neutral organic chemicals. The first model, referred to here as the 2-parameter partitioning model (PPM), exploits a linear free energy relationship (LFER) of skin permeability coefficient with a linear combination of partition coefficients for octanol–water and air–water systems. The second model is based on the retention time information of nonpolar analytes on comprehensive two-dimensional gas chromatography (GC × GC). The PPM successfully explained variability in the skin permeability data (n = 175) with R 2 = 0.82 and root mean square error (RMSE) = 0.47 log unit. In comparison, the US-EPA’s model DERMWIN™ exhibited an RMSE of 0.78 log unit. The Zhang model—a 5-parameter LFER equation based on experimental Abraham solute descriptors (ASDs)—performed slightly better with an RMSE value of 0.44 log unit. However, the Zhang model is limited by the scarcity of experimental ASDs. The GC × GC model successfully explained the variance in skin permeability data of nonpolar chemicals (n = 79) with R 2 = 0.90 and RMSE = 0.23 log unit. The PPM can easily be implemented in US-EPA’s Estimation Program Interface Suite (EPI Suite™). The GC × GC model can be applied to the complex mixtures of nonpolar chemicals.

Studies during the past 50 years have characterized the carcinogenicity and mutagenicity of extractable organic material (EOM) of particulate matter (PM) in ambient air and from combustion emissions. We have summarized conclusions from these studies and present data supporting those conclusions for 50 combustion emissions, including carcinogenic potencies on mouse skin (papillomas/mouse/mg EOM), mutagenic potencies (revertants/μg EOM) in the Salmonella (Ames) mutagenicity assay, and mutagenicity emission factors (revertants/kg fuel or revertants/MJthermal) in Salmonella. Mutagenic potencies of EOM from PM in ambient air and combustion emissions span 1–2 orders of magnitude, respectively. In contrast, the revertants/m3 span >5 orders of magnitude due to variable PM concentrations in ambient air. Carcinogenic potencies of EOM from combustion emissions on mouse skin and EOM‐associated human lung cancer risk from those emissions both span ~3 orders of magnitude and are highly associated. The ubiquitous presence of polycyclic aromatic hydrocarbons (PAHs), nitroarenes, and aromatic amines results in mutagenic and carcinogenic potencies of PM that span only 1–3 orders of magnitude; most PM induces primarily G to T mutations. Mutagenicity emission factors of combustion emissions span 3–5 orders of magnitude and correlate with PAH emission factors (r > 0.9). Mutagenicity emission factors were largely a function of how material was burned (highly efficient modern combustors versus open burning) rather than what materials were burned. Combustion systems that minimize kinetic and mass‐transfer limitations and promote complete oxidation also minimize the mutagenicity of their emissions. This fundamental engineering principle can inform environmental and public health assessments of combustion emissions. [ABSTRACT FROM AUTHOR]

Background Low-dose persistent organic pollutants (POPs), especially organochlorine pesticides (OCPs), have emerged as a new risk factor of many chronic diseases. As serum concentrations of POPs in humans are mainly determined by both their release from adipose tissue to circulation and their elimination from circulation, management of these internal pathways may be important in controlling the serum concentrations of POPs. As habitual physical activity can increase the elimination of POPs from circulation, we evaluated whether chronic physical activity is related to low serum POP concentrations. Methods A cross-sectional study of 1,850 healthy adults (age ≥20 years) without cardio-metabolic diseases who participated in the U.S. National Health and Nutrition Examination Survey 1999 to 2004 was conducted. Information on moderate or vigorous leisure-time physical activity was obtained based on questionnaires. Serum concentrations of OCPs and polychlorinated biphenyls were investigated as typical POPs. Results Serum concentrations of OCPs among physically active subjects were significantly lower than those among physically inactive subjects (312.8 ng/g lipid vs. 538.0 ng/g lipid, P

Ethnopharmacological Relevance: Trametes Robiniophila Murr, commonly known as Huaier, has been extensively documented in ethnopharmacology research in China. Huaier has a long history of clinical usage spanning over 1000 years in China. Traditional clinical application records demonstrate the wide utilization of Huaier for treating various cancers and enhancing the autoimmunity of tumor patients., Aim of the Review: The present study provides a comprehensive review of the traditional uses, phytochemical constituents, pharmacological activities, anti-tumor mechanism, and potential applications of Huaier, thereby offering valuable insights for the further development and utilization of this natural product., Materials and Methods: This study employed the keywords "Trametes Robiniophila Murr" and "Huaier" to retrieve relevant information on Huaier from various databases, including PubMed, Web of Science, Springer, Science Direct, ACS, Wiley, CNKI, Baidu Scholar, Google Scholar, and ancient materia medica., Results: Trametes Robiniophila Murr (Huaier), a traditional Chinese medicine, has demonstrated significant efficacy in the clinical treatment of various tumors. The primary bioactive constituents of Huaier consist of fungal-derived compounds, including polysaccharides, proteins, ketones, alkaloids, and minerals. The research findings demonstrate that Huaier serves as a reliable adjunctive therapeutic agent by effectively inhibiting cancer cell proliferation, inducing apoptosis in cancer cells, suppressing tumor metastasis, regulating tumor stem cells and immune function. Therefore, it exerts a potent anti-tumor effect when used in conjunction with conventional anti-cancer therapies., Conclusions: The analysis of traditional uses, phytochemical composition, and pharmacological activity reveals that Huaier exhibits significant potential as a medicinal plant with diverse pharmacological effects. Owing to its numerous advantages, Huaier holds immense promise for application in the domains of tumor prevention and treatment, enhancing both survival time and quality of life among cancer patients., Competing Interests: Declaration of competing interest We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled., (Copyright © 2024 Elsevier B.V. All rights reserved.)

UnlabelledElectronic (e)-cigarette use is rapidly rising, with 20 % of Americans ages 25-44 now using these drug delivery devices. E-cigarette users expose their airways, cells of host defense, and colonizing bacteria to e-cigarette vapor (EV). Here, we report that exposure of human epithelial cells at the air-liquid interface to fresh EV (vaped from an e-cigarette device) resulted in dose-dependent cell death. After exposure to EV, cells of host defense-epithelial cells, alveolar macrophages, and neutrophils-had reduced antimicrobial activity against Staphylococcus aureus (SA). Mouse inhalation of EV for 1 h daily for 4 weeks led to alterations in inflammatory markers within the airways and elevation of an acute phase reactant in serum. Upon exposure to e-cigarette vapor extract (EVE), airway colonizer SA had increased biofilm formation, adherence and invasion of epithelial cells, resistance to human antimicrobial peptide LL-37, and up-regulation of virulence genes. EVE-exposed SA were more virulent in a mouse model of pneumonia. These data suggest that e-cigarettes may be toxic to airway cells, suppress host defenses, and promote inflammation over time, while also promoting virulence of colonizing bacteria.Key messageAcute exposure to e-cigarette vapor (EV) is cytotoxic to airway cells in vitro. Acute exposure to EV decreases macrophage and neutrophil antimicrobial function. Inhalation of EV alters immunomodulating cytokines in the airways of mice. Inhalation of EV leads to increased markers of inflammation in BAL and serum. Staphylococcus aureus become more virulent when exposed to EV.

Many of the newly produced and registered substances are complex mixtures or substances of unknown or variable composition, complex reaction products, and biological materials (UVCBs). The latter often consist of a large number of constituents, some of them difficult‐to‐identify constituents, which complicates their (eco)toxicological assessment. In the present study, through a series of examples, different scenarios for selection of representatives via hierarchical clustering of UVCB constituents are exemplified. Hierarchical clustering allows grouping of the individual chemicals into small sets, where the constituents are similar to each other with respect to more than one criterion. To this end, various similarity criteria and approaches for selection of representatives are developed and analyzed. Two types of selection are addressed: (1) selection of the most "conservative" constituents, which could be also used to support prioritization of UVCBs for evaluation, and (2) obtaining of a small set of chemical representatives that covers the structural and metabolic diversity of the whole target UVCBs or a mixture that can then be evaluated for their environmental and (eco)toxicological properties. The first step is to generate all plausible UVCB or mixture constituents. It was found that the appropriate approach for selecting representative constituents depends on the target endpoint and physicochemical parameters affecting the endpoint of interest. Environ Toxicol Chem 2021;40:3205–3218. © 2021 SETAC [ABSTRACT FROM AUTHOR]

Crude-Oil-to-Chemicals (COTC) is a novel concept in the oil industry in which the production of base chemicals is preferred over fuels. This concept requires an intensive integration of refinery and petrochemical operations and, in most cases, hydroconversion and steam cracking play an essential role. In the present work, particularly the role of hydroconversion is assessed in selected COTC scenarios via a simulation framework based on fundamental modeling that seamlessly integrates a Single-Event Microkinetics description of the cracking reactions with a molecular reconstruction strategy based on Shannon Entropy maximization for determining the detailed feedstock composition. Dealkylation and ring opening reactions have been identified as the crucial ones to produce good steam cracker feeds, i.e., mixtures of paraffins in the C3-C21 range, especially n-paraffins. Simulation results show that for a typical VGO paraffins yield in the desired fraction increases from 8.9% wt/wt to 19.6% wt/wt with an increase of +5 kJ/mol in the acidity strength of the catalyst (Δ H prot ) and an increase of +10 °C in the operation temperature. In general, it was found that the yield of the total C3-C21 fraction increased by +1.42 wt% per kJ/mol decrease of the Δ H prot of the catalyst, while per °C temperature increase the yield of the same fraction increased by of + 0.46 wt%. [Display omitted] • Molecule/Bulk-Property description of streams unravels hydrocracking exotic feeds. • Fundamental kinetics relates feed, catalyst and process conditions into products. • Branches isomerization and dealkylation are key reactions in COTC configurations. • Mono-Naphthenics hydrocracking is key to convert fossils to steam cracking feedstocks. • C3-C21 fraction and its n-paraffins proportion increases at higher severities. [ABSTRACT FROM AUTHOR]

Urinary mutagenicity reflects systemic exposure to complex mixtures of genotoxic/carcinogenic agents and is linked to tumor development. Coal combustion emissions (CCE) and diesel engine exhaust (DEE) are associated with cancers of the lung and other sites, but their influence on urinary mutagenicity is unclear. We investigated associations between exposure to CCE or DEE and urinary mutagenicity. In two separate cross‐sectional studies of nonsmokers, organic extracts of urine were evaluated for mutagenicity levels using strain YG1041 in the Salmonella (Ames) mutagenicity assay. First, we compared levels among 10 female bituminous (smoky) coal users from Laibin, Xuanwei, China, and 10 female anthracite (smokeless) coal users. We estimated exposure–response relationships using indoor air concentrations of two carcinogens in CCE relevant to lung cancer, 5‐methylchrysene (5MC), and benzo[a]pyrene (B[a]P). Second, we compared levels among 20 highly exposed male diesel factory workers and 15 unexposed male controls; we evaluated exposure‐response relationships using elemental carbon (EC) as a DEE‐surrogate. Age‐adjusted linear regression was used to estimate associations. Laibin smoky coal users had significantly higher average urinary mutagenicity levels compared to smokeless coal users (28.4 ± 14.0 SD vs. 0.9 ± 2.8 SD rev/ml‐eq, p = 2 × 10−5) and a significant exposure‐response relationship with 5MC (p = 7 × 10−4). DEE‐exposed workers had significantly higher urinary mutagenicity levels compared to unexposed controls (13.0 ± 10.1 SD vs. 5.6 ± 4.4 SD rev/ml‐eq, p =.02) and a significant exposure‐response relationship with EC (p‐trend = 2 × 10−3). Exposure to CCE and DEE is associated with urinary mutagenicity, suggesting systemic exposure to mutagens, potentially contributing to cancer risk and development at various sites. [ABSTRACT FROM AUTHOR]

The production of chlorine by the chlor-alkali process using graphite electrodes was one of the largest sources of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/PCDFs) in history with estimates in the kg TEQ range for individual factories. In addition, the chlorine production predecessor processes in the former Leblanc soda factories generated large amounts of PCDD/PCDFs, also in kg TEQ range for individual sites. In both processes coal tar, used as pitch binder for electrodes in the chlor-alkali process or tars for sealing chlorine chambers, was the major source for PCDD/PCDFs formation. The complex PAH mixture in the tars which were chlorinated in the processes contained approx. 1% dibenzofuran. Therefore in this study we screened the full range of chlorinated aromatic and heteroaromatic compounds in contaminated soils from former chlor-alkali plants in Germany and Japan as well as from a German Leblanc factory, using high resolution time-of-flight mass spectrometry GC-HR-TOF-MS. At all three sites the full range of unintentionally produced persistent organic pollutants (POPs) listed in the Stockholm Convention (PCDFs, PCDDs, PCBs, PCNs, HCB, HCBD and PeCBz) were present at high ppb levels and TEQ was up to several 100,000 ng/kg soil in hot spot areas. Additionally, a wide range of other polychlorinated (PC-) PAHs (PC-phenanthrene/anthracene, PC-pyrene/fluoranthene, PC-benzo(a)anthracene/chrysene) were detected. Some of these compound classes were present in one to two order of magnitude higher concentrations compared to PCDFs. Furthermore, polychlorinated methyl-dibenzofurans, polychlorinated dimethyl-/ethyl-dibenzofurans, and polychlorinated carbazoles – the N-analogue of dibenzofuran - were detected at levels comparable to PCDFs at all three sites.Polychlorinated benzonitriles were detected in addition to chlorobenzenes as monoaromatic pollutant. Since all three factories have stopped production 50–120 years ago, all detected chlorinated aromatics can be regarded as very persistent. The technologies have been used in several hundred locations globally. These (former) chlorine production sites should be assessed for contamination and their contemporary threat to humans and the environment should be evaluated. The toxicity of most of these polychlorinated PAHs and hetero-PAHs is unknown but due to their related structures, similar toxicity profiles can be expected and need to be investigated. Furthermore, all processes where chlorine and complex organic material are present should be screened for the entire resulting chlorinated pollutant mixture, the detailed fingerprints should be documented, and the overall toxicological risk assessed for individual processes to inform policy making.

Chronic liver diseases affect more than 1 billion people worldwide and represent one of the main public health issues. Nonalcoholic fatty liver disease (NAFLD) accounts for the majority of mortal cases, while there is no currently approved therapeutics for its treatment. One of the prospective approaches to NAFLD therapy is to use a mixture of natural compounds. They showed effectiveness in alleviating NAFLD-related conditions including steatosis, fibrosis, etc. However, understanding the mechanism of action of such mixtures is important for their rational application. In this work, we propose a new dereplication workflow for deciphering the mechanism of action of the lignin-derived natural compound mixture. The workflow combines the analysis of molecular components with high-resolution mass spectrometry, selective chemical tagging and deuterium labeling, liver tissue penetration examination, assessment of biological activity in vitro, and computational chemistry tools used to generate putative structural candidates. Molecular docking was used to propose the potential mechanism of action of these structures, which was assessed by a proteomic experiment.

High-performance thin-layer chromatography hyphenated with planar multiplex bioassays and high-resolution tandem mass spectrometry contributes to the non-target detection or even identification of active compounds in complex mixtures such as food, feed, cosmetics, commodities, and environmental samples. It can be used to discover previously unknown harmful or active substances in complex samples and to tentatively assign molecular formulas. This method is already faster than the commonly used in vitro assays along with liquid chromatographic separations, but overnight cell cultivation still prevents a planar bioassay from being performed within one day. There is also still potential for optimization in terms of sustainability. To achieve this, the planar bioassay protocols for the detection of androgen-like and estrogen-like compounds were harmonized. The successful minimization of the cell culture volume enabled accelerated cell cultivation, which allowed the bioassay to be performed within one day. This was considered a milestone achieved, as up to 23 samples per plate can now be analyzed from the start of cultivation to the biological endpoint on the same day. Doubling the substrate amount and increasing the pH of the silica gel layer led to a more sensitive and selective bioassay due to the enhanced fluorescence of the formed end-product. The faster and more sustainable bioassay protocol was applied to complex samples such as sunscreen and red wine to detect estrogen-like compounds. The developed method was validated by comparison with a standard method., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Nuclear magnetic resonance (NMR) based 13 C tracing has broad applications across medical and environmental research. As many biological and environmental samples are heterogeneous, they experience considerable spectral overlap and relatively low signal. Here a 1D 1 H- 12 C/ 13 C is introduced that uses "in-phase/opposite-phase" encoding to simultaneously detect and discriminate both protons attached to 12 C and 13 C at full 1 H sensitivity in every scan. Unlike traditional approaches that focus on the 12 C/ 13 C satellite ratios in a 1 H spectrum, this approach creates separate sub-spectra for the 12 C and 13 C bound protons. These spectra can be used for both quantitative and qualitative analysis of complex samples with significant spectral overlap. Due to the presence of the 13 C dipole, faster relaxation of the 1 H- 13 C pairs results in slight underestimation compared to the 1 H- 12 C pairs. However, this is easily compensated for, by collecting an additional reference spectrum, from which the absolute percentage of 13 C can be calculated by difference. When combined with the result, 12 C and 13 C percent enrichment in both 1 H- 12 C and 1 H- 13 C fractions are obtained. As the approach uses isotope filtered 1 H NMR for detection, it retains nearly the same sensitivity as a standard 1 H spectrum. Here, a proof-of-concept is performed using simple mixtures of 12 C and 13 C glucose, followed by suspended algal cells with varying 12 C / 13 C ratios representing a complex mixture. The results consistently return 12 C/ 13 C ratios that deviate less than 1 % on average from the expected. Finally, the sequence was used to monitor and quantify 13 C% enrichment in Daphnia magna neonates which were fed a 13 C diet over 1 week. The approach helped reveal how the organisms utilized the 12 C lipids they are born with vs. the 13 C lipids they assimilate from their diet during growth. Given the experiments simplicity, versatility, and sensitivity, we anticipate it should find broad application in a wide range of tracer studies, such as fluxomics, with applications spanning various disciplines., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Our understanding of how microbes respond to micropollutants, such as pesticides, is almost wholly based on single-species responses to individual chemicals. However, in natural environments, microbes experience multiple pollutants simultaneously. Here we perform a matrix of multi-stressor experiments by assaying the growth of model and non-model strains of bacteria in all 255 combinations of 8 chemical stressors (antibiotics, herbicides, fungicides and pesticides). We found that bacterial strains responded in different ways to stressor mixtures, which could not be predicted simply from their phylogenetic relatedness. Increasingly complex chemical mixtures were both more likely to negatively impact bacterial growth in monoculture and more likely to reveal net interactive effects. A mixed co-culture of strains proved more resilient to increasingly complex mixtures and revealed fewer interactions in the growth response. These results show predictability in microbial population responses to chemical stressors and could increase the utility of next-generation eco-toxicological assays., (© 2024. The Author(s).)

In response to the demand for advanced purification of industrial secondary effluent, a new method has been developed for treating chlorophenol wastewater using the novel ceramsite-based Ti/SnO 2 -Sb particle electrodes (Ti/SnO 2 -Sb/CB) enhanced electrocatalytic denitrification biofilter (EDNBF-P) to achieve removal of chlorophenols (CPs), denitrification, and reduction of effluent toxicity. The results showed that significantly improved CPs and TN removal efficiency at low COD/N compared to conventional denitrification biofilter, with CPs removal rates increasing by 0.33%-59.27% and TN removal rates increasing by 12.53%-38.92%. Under the conditions of HRT = 2h, 3V voltage, charging times = 12h, and 25 °C, the concentrations of the CPs in the effluent of EDNBF-P were all below 1 mg/L, the TN concentration was below 15 mg/L, while the effluent toxicity reached the low toxicity level. Additionally, the Ti/SnO 2 -Sb/CB particle electrodes effectively alleviated the accumulation of NO 2 - -N caused by applied voltage. The Silanimonas, Pseudomonas and Rhodobacter was identified as the core microorganism for denitrification and toxicity reduction. This study validated that EDNBF-P could achieve synergistic treatment of CPs and TN through electrocatalysis and microbial degradation, providing a methodological support for achieving advanced purification of chlorophenol wastewater with low COD/N in industrial applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Laccase is a superfamily of ligninolytic enzymes known to degrade a wide variety of xenobiotics, including synthetic dyes. Congo Red (CR) has a diazo dye function, carcinogenic and mutagenic potential, and is currently applied in clinical analysis. The objective of this work was to produce and characterize the crude extract of Lentinus sp . in semi-solid fermentation (FSS) and perform in vitro and in silico studies to assess the potential of the crude extract to discolor the CR dye. Laccase activity was determined using ABTS as substrate and characterized. The in vitro discoloration was carried out using experimental design 2 2 at room temperature and monitored at 340 nm for 24h. Molecular docking and molecular dynamics simulations were performed between laccase and CR. The maximum laccase activity production was 29.63 U L -1 with six days of FSS. The optimal temperature and pH were 50 °C and 3.0, respectively. Discoloration of the CR dye was obtained only in tests containing CuSO 4 . Laccase formed stable complexes with the dye, presenting negative binding energy values ranging from -70.94 to -63.16 kcal mol -1 and the occurrence of seven hydrogen bonds. Molecular dynamics results showed the stability of the system (RMSD ranging from 1.0 to 2.5 Ä) and protein-ligand interaction along simulation. RMSF values pointed residues at the end of chains A (residues 300 to 305, 480 to 500) and B (residues 650 to 655 and 950 to 1000) as the most flexible regions of the laccase. This study highlighted the enzymatic action in the bioremediation of CR in vitro in agreement with the in silico simulations that demonstrate the enzyme potential.Communicated by Ramaswamy H. Sarma.

Waterborne contaminants were monitored in 69 tributaries of the Laurentian Great Lakes in 2010 and 2014 using semipermeable membrane devices (SPMDs) and polar organic chemical integrative samplers (POCIS). A risk‐based screening approach was used to prioritize chemicals and chemical mixtures, identify sites at greatest risk for biological impacts, and identify potential hazards to monitor at those sites. Analyses included 185 chemicals (143 detected) including polycyclic aromatic hydrocarbons (PAHs), legacy and current‐use pesticides, fire retardants, pharmaceuticals, and fragrances. Hazard quotients were calculated by dividing detected concentrations by biological effect concentrations reported in the ECOTOX Knowledgebase (toxicity quotients) or ToxCast database (exposure–activity ratios [EARs]). Mixture effects were estimated by summation of EAR values for chemicals that influence ToxCast assays with common gene targets. Nineteen chemicals—atrazine, N,N‐diethyltoluamide, di(2‐ethylhexyl)phthalate, dl‐menthol, galaxolide, p‐tert‐octylphenol, 3 organochlorine pesticides, 3 PAHs, 4 pharmaceuticals, and 3 phosphate flame retardants—had toxicity quotients >0.1 or EARs for individual chemicals >10–3 at 10% or more of the sites monitored. An additional 4 chemicals (tributyl phosphate, triethyl citrate, benz[a]anthracene, and benzo[b]fluoranthene) were present in mixtures with EARs >10–3. To evaluate potential apical effects and biological endpoints to monitor in exposed wildlife, in vitro bioactivity data were compared to adverse outcome pathway gene ontology information. Endpoints and effects associated with endocrine disruption, alterations in xenobiotic metabolism, and potentially neuronal development would be relevant to monitor at the priority sites. The EAR threshold exceedance for many chemical classes was correlated with urban land cover and wastewater effluent influence, whereas herbicides and fire retardants were also correlated to agricultural land cover. Environ Toxicol Chem 2021;40:2165–2182. Published 2021. This article is a U.S. Government work and is in the public domain in the USA. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC. [ABSTRACT FROM AUTHOR]

The human diet consists of a complex mixture of components. To realistically assess dietary impacts on health, new statistical tools that can better address nonlinear, collinear, and interactive relationships are necessary. Using data from 1,928 healthy participants in the Coronary Artery Risk Development in Young Adults (CARDIA) cohort (1985–2006), we explored the association between 12 dietary factors and 10-year predicted risk of atherosclerotic cardiovascular disease (ASCVD) using an innovative approach, Bayesian kernel machine regression (BKMR). Employing BKMR, we found that among women, unprocessed red meat was most strongly related to the outcome: An interquartile range increase in unprocessed red meat consumption was associated with a 0.07-unit (95% credible interval: 0.01, 0.13) increase in ASCVD risk when intakes of other dietary components were fixed at their median values (similar results were obtained when other components were fixed at their 25th and 75th percentile values). Among men, fruits had the strongest association: An interquartile range increase in fruit consumption was associated with −0.09-unit (95% credible interval (CrI): −0.16, −0.02), −0.10-unit (95% CrI: −0.16, −0.03), and −0.11-unit (95% CrI: −0.18, −0.04) lower ASCVD risk when other dietary components were fixed at their 25th, 50th (median), and 75th percentile values, respectively. Using BKMR to explore the complex structure of the total diet, we found distinct sex-specific diet-ASCVD relationships and synergistic interaction between whole grain and fruit consumption. [ABSTRACT FROM AUTHOR]

Background. In risk assessment, genotoxicity is a key factor to determine the safety for the consumer. Most in vitro genotoxicity assays were developed for the assessment of pure substances. However, in recent years more attention has been given to complex mixtures, where usually low amounts of a substance are present. For high-throughput screening, a toxicologically sensitive assay should be used, covering a broad range of genotoxic substances and detecting them at low concentrations. HepG2 cells have been recommended as one of the prime candidates for genotoxicity testing, as they are p53 competent, less prone towards cytotoxic effects and tend to have some metabolic activity. Methods. A HepG2 liver cell line was characterized for its suitability for genotoxicity assessment. For this, a luciferase based reporter gene assay revolving around the p53 pathway was validated for the analysis of pure substances and of complex mixtures. Further, the cell’s capability to detect genotoxins correctly with and without an exogenous metabolizing system, namely rat liver S9, was assessed. Results. The assay proved to have a high toxicological sensitivity (87.5%) and specificity (94%). Further, the endogenous metabolizing system of the HepG2 cells was able to detect some genotoxins, which are known to depend on an enzymatic system. When complex mixtures were added this did not lead to any adverse effects concerning the assays performance and cytotoxicity was not an issue. Discussion. The HepGentox proved to have a high toxicological sensitivity and speci- ficity for the tested substances, with similar or even lower lowest effective concentration (LEC) values, compared to other regulatory mammalian assays. This combines some important aspects in one test system, while also being less time and material consuming and covering several genotoxicity endpoints. As the assay performs well with and without an exogenous metabolizing system, no animal liver fractions have to be used, which application is discussed controversially and is considered to be expensive and laborious in sample testing. Because of this, the HepGentox is suitable for a cost- efficient first screening approach to obtain important information with human cells for further approaches, with a relatively fast and easy method. Therefore, the HepGentox is a promising assay to detect genotoxic substances correctly in complex mixtures even at low concentrations, with the potential for a high throughput application. In a nutshell, as part of an in vitro bioassay test battery, this assay could provide valuable information for complex mixtures. [ABSTRACT FROM AUTHOR]

Background In risk assessment, genotoxicity is a key factor to determine the safety for the consumer. Most in vitro genotoxicity assays were developed for the assessment of pure substances. However, in recent years more attention has been given to complex mixtures, where usually low amounts of a substance are present. For high-throughput screening, a toxicologically sensitive assay should be used, covering a broad range of genotoxic substances and detecting them at low concentrations. HepG2 cells have been recommended as one of the prime candidates for genotoxicity testing, as they are p53 competent, less prone towards cytotoxic effects and tend to have some metabolic activity. Methods A HepG2 liver cell line was characterized for its suitability for genotoxicity assessment. For this, a luciferase based reporter gene assay revolving around the p53 pathway was validated for the analysis of pure substances and of complex mixtures. Further, the cell’s capability to detect genotoxins correctly with and without an exogenous metabolizing system, namely rat liver S9, was assessed. Results The assay proved to have a high toxicological sensitivity (87.5%) and specificity (94%). Further, the endogenous metabolizing system of the HepG2 cells was able to detect some genotoxins, which are known to depend on an enzymatic system. When complex mixtures were added this did not lead to any adverse effects concerning the assays performance and cytotoxicity was not an issue. Discussion The HepGentox proved to have a high toxicological sensitivity and specificity for the tested substances, with similar or even lower lowest effective concentration (LEC) values, compared to other regulatory mammalian assays. This combines some important aspects in one test system, while also being less time and material consuming and covering several genotoxicity endpoints. As the assay performs well with and without an exogenous metabolizing system, no animal liver fractions have to be used, which application is discussed controversially and is considered to be expensive and laborious in sample testing. Because of this, the HepGentox is suitable for a cost-efficient first screening approach to obtain important information with human cells for further approaches, with a relatively fast and easy method. Therefore, the HepGentox is a promising assay to detect genotoxic substances correctly in complex mixtures even at low concentrations, with the potential for a high throughput application. In a nutshell, as part of an in vitro bioassay test battery, this assay could provide valuable information for complex mixtures.

The (bio)pharmaceutical industry is rapidly moving towards complex drug modalities that require a commensurate level of analytical enabling technologies that can be deployed at a fast pace. Unsystematic method development and unnecessary manual intervention remain a major barrier towards a more efficient deployment of meaningful analytical assay across emerging modalities. Digitalization and automation are key to streamline method development and enable rapid assay deployment. This review discusses the use of computer-assisted multifactorial chromatographic method development strategies for fast-paced downstream characterization and purification of biopharmaceuticals. Various chromatographic techniques such as reversed-phase liquid chromatography (RPLC), hydrophilic interaction liquid chromatography (HILIC), ion exchange chromatography (IEX), hydrophobic interaction chromatography (HIC), and supercritical fluid chromatography (SFC) are addressed and critically reviewed. The most significant parameters for retention mechanism modelling, as well as mapping the separation landscape for optimal chromatographic selectivity and resolution are also discussed. Furthermore, several computer-assisted approaches for optimization and development of chromatographic methods of therapeutics, including linear, nonlinear, and multifactorial modelling are outlined. Finally, the potential of the chromatographic modelling and computer-assisted optimization strategies are also illustrated, highlighting substantial productivity improvements, and cost savings while accelerating method development, deployment and transfer processes for therapeutic analysis in industrial settings. [Display omitted] • Computer-Assisted multifactorial chromatographic strategies were addressed. • Using proper linear and non-linear models were discussed. • Applications in various chromatographic techniques are critically reviewed. • Important parameters for retention mechanism modelling are demonstrated. • Computer-Assisted optimization strategies are highlighted for generic methods. [ABSTRACT FROM AUTHOR]

The experimental values of skin permeability coefficients, required for dermal exposure assessment, are not readily available for many chemicals. The existing estimation approaches are either less accurate or require many parameters that are not readily available. Furthermore, current estimation methods are not easy to apply to complex environmental mixtures. We present two models to estimate the skin permeability coefficients of neutral organic chemicals. The first model, referred to here as the 2-parameter partitioning model (PPM), exploits a linear free energy relationship (LFER) of skin permeability coefficient with a linear combination of partition coefficients for octanol–water and air–water systems. The second model is based on the retention time information of nonpolar analytes on comprehensive two-dimensional gas chromatography (GC × GC). The PPM successfully explained variability in the skin permeability data (n = 175) with R2 = 0.82 and root mean square error (RMSE) = 0.47 log unit. In comparison, the US-EPA's model DERMWIN™ exhibited an RMSE of 0.78 log unit. The Zhang model—a 5-parameter LFER equation based on experimental Abraham solute descriptors (ASDs)—performed slightly better with an RMSE value of 0.44 log unit. However, the Zhang model is limited by the scarcity of experimental ASDs. The GC × GC model successfully explained the variance in skin permeability data of nonpolar chemicals (n = 79) with R2 = 0.90 and RMSE = 0.23 log unit. The PPM can easily be implemented in US-EPA's Estimation Program Interface Suite (EPI Suite™). The GC × GC model can be applied to the complex mixtures of nonpolar chemicals. [ABSTRACT FROM AUTHOR]