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The biofilm architecture is significantly influenced by external environmental conditions. Biofilms grown on drinking water distribution systems (DWDS) are exposed to environmental contaminants, including parabens, and disinfection strategies, such as chlorine. Although changes in biofilm density and culturability from chemical exposure are widely reported, little is known about the effects of parabens and chlorine on biofilm morphology and architecture. This is the first study evaluating architectural changes in Stenotrophomonas maltophilia colony biofilms (representatives of bacterial communities presented in DWDS) induced by the exposure to methylparaben (MP) at environmental (15 μg/L) and in-use (15 mg/L) concentrations, and chlorine at 5 mg/L, using widefield epi-fluorescence mesoscopy with Mesolens. The GFP fluorescence of colony biofilms allowed the visualization of internal structures and Nile Red fluorescence permitted the inspection of the distribution of lipids. Our data show that exposure to MP triggers physiological and morphological adaptation in mature colony biofilms by increasing the complexity of internal structures, which may confer protection to embedded cells from external chemical molecules. These architectural modifications include changes in lipid distribution as an adaptive response to MP exposure. Although chlorine exposure affected colony biofilm diameter and architecture, the colony roundness was completely affected by the simultaneous presence of MP and chlorine. This work is pioneer in using Mesolens to highlight the risks of exposure to emerging environmental contaminants (MP), by affecting the architecture of biofilms formed by drinking water (DW) bacteria, even when combined with routine disinfection strategies., 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. Published by Elsevier B.V.)

Conventional wastewater treatment methods cannot completely remove the ultraviolet (UV) filters or dissolved organic matter. The transformation characteristics of these substances during chlorination disinfection and the varying species-specific toxicities of their combinations remain unclear. Here, Daphnia magna and zebrafish were exposed to benzophenone-3 (BP-3) and humic acid (HA) before and after chlorination disinfection. The results from chemical indicators showed that chlorination treatment decreased UV254 values and changed the intensity of parallel factors in three-dimensional fluorescence. Based on chemical analysis, the chlorine concentration and chlorination time for the toxicity experiments were set at 5 mg/L and 6 h, respectively. Exposure to HA and BP-3 before and after chlorination decreased the heart rate (by 1.37-28.12 %) in both species. However, species-specific responses, including survival rate, swimming distance, and expression of genes related to neurodevelopment, growth, and oxidative stress, were induced by chlorination. Chlorination reduced the impact of HA exposure but worsened the effects of HA and BP-3 co-exposure on D. magna. However, in zebrafish, the toxic effects intensified in most of the exposure groups after chlorination. Correlation analysis showed that the parallel factors of three-dimensional fluorescence were correlated with toxic effects on zebrafish, whereas UV254 was more significantly correlated with toxic effects on D. magna. This study provides insights into the combined toxicity of UV filters and dissolved organic matter in different aquatic organisms during chlorination, which is useful for risk control and optimization of the chlorination process., 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 B.V. All rights reserved.)

Ultrafiltration (UF) is widely used in drinking water plants; however, membrane fouling is unavoidable. Natural organic matter (NOM) is commonly considered as an important pollutant that causes membrane fouling. Herein, we proposed VUV/H 2 O 2 as a UF pretreatment and used UV/H 2 O 2 for comparison. Compared to UV/H 2 O 2 , the VUV/H 2 O 2 system presented superior NOM removal. In the VUV/H 2 O 2 system, the steady-state concentration of HO• was approximately twice that in the UV/H 2 O 2 system, which was ascribed to the promoting effect of the 185 nm photons. Specifically, 185 nm photons promoted HO• generation by decomposing mainly H 2 O at a low H 2 O 2 dose or by decomposing mainly H 2 O 2 at a high H 2 O 2 dose. The VUV/H 2 O 2 pretreatment also demonstrated better membrane fouling mitigation performance than did UV/H 2 O 2 . An increase in the H 2 O 2 dose promoted HO• generation, thereby enhancing the performance of NOM degradation and membrane fouling alleviation and shifting the major membrane fouling mechanism from cake filtration to standard blocking. The VUV/H 2 O 2 (0.60 mM) pretreatment effectively reduced disinfection byproducts (DBPs) formation during chlorine disinfection. Additionally, the oxidant H 2 O 2 affected the membrane surface morphology and performance but had no evident effect on the mechanical properties. In actual water treatment, the VUV/H 2 O 2 pretreatment exhibited better performance than the UV/H 2 O 2 pretreatment in easing membrane fouling, ameliorating water quality, and reducing DBPs formation and acute toxicity., 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 B.V. All rights reserved.)

Adenosine triphosphate (ATP) can be released into the extracellular milieu from various types of cells in response to a wide range of physical or chemical stresses. In the respiratory tract, extracellular ATP is recognized as an important signal molecule and trigger of airway inflammation. Chlorine (Cl 2 ), sulfur dioxide (SO 2 ), and ammonia (NH 3 ) are potent irritant gases and common industrial air pollutants due to their widespread uses as chemical agents. This study was carried out to determine if acute inhalation challenges of these irritant gases, at the concentration and duration simulating the accidental exposures to these chemical gases in industrial operations, triggered the release of ATP in the rat respiratory tract; and if so, whether the level of ATP in bronchoalveolar lavage fluid (BALF) evoked by inhalation challenge of a given irritant gas was elevated by chronic allergic airway inflammation. Our results showed: 1 ) inhalation of these irritant gases caused significant increases in the ATP level in BALF, and the magnitude of evoked ATP release was in the order of Cl 2 > SO 2 > NH 3 . 2 ) Chronic airway inflammation induced by ovalbumin-sensitization markedly elevated the ATP level in BALF during baseline (breathing room air) but did not potentiate the release of ATP in the lung triggered by inhalation challenges of these irritant gases. These findings suggested a possible involvement of the ATP release in the lung in the regulation of overall airway responses to acute inhalation of irritant gases and the pathogenesis of chronic allergic airway inflammation. NEW & NOTEWORTHY Extracellular adenosine triphosphate (ATP) is a contributing factor and signaling molecule of airway inflammation. This study demonstrated for the first time that the ATP release in the lung was markedly elevated after acute inhalation challenges of three common industrial air pollutants; the order of the response magnitude was chlorine > sulfur dioxide > ammonia. These findings provided new information and improved our understanding of the adverse pulmonary effects caused by accidental inhalation exposures to these irritant gases.

As a regulator of alveolo-capillary barrier integrity, Transient Receptor Potential Vanilloid 4 (TRPV4) antagonism represents a promising strategy for reducing pulmonary edema secondary to chemical inhalation. In an experimental model of acute lung injury induced by exposure of anesthetized swine to chlorine gas by mechanical ventilation, the dose-dependent effects of TRPV4 inhibitor GSK2798745 were evaluated. Pulmonary function and oxygenation were measured hourly; airway responsiveness, wet-to-dry lung weight ratios, airway inflammation, and histopathology were assessed 24 h post-exposure. Exposure to 240 parts per million (ppm) chlorine gas for ≥50 min resulted in acute lung injury characterized by sustained changes in the ratio of partial pressure of oxygen in arterial blood to the fraction of inspiratory oxygen concentration (PaO 2 /FiO 2 ), oxygenation index, peak inspiratory pressure, dynamic lung compliance, and respiratory system resistance over 24 h. Chlorine exposure also heightened airway response to methacholine and increased wet-to-dry lung weight ratios at 24 h. Following 55-min chlorine gas exposure, GSK2798745 marginally improved PaO 2 /FiO 2 , but did not impact lung function, airway responsiveness, wet-to-dry lung weight ratios, airway inflammation, or histopathology. In summary, in this swine model of chlorine gas-induced acute lung injury, GSK2798745 did not demonstrate a clinically relevant improvement of key disease endpoints.

Chlorine gas (Cl 2 ) has been repeatedly used as a chemical weapon, first in World War I and most recently in Syria. Life-threatening Cl 2 exposures frequently occur in domestic and occupational environments, and in transportation accidents. Modeling the human etiology of Cl 2 -induced acute lung injury (ALI), forensic biomarkers, and targeted countermeasures development have been hampered by inadequate large animal models. The objective of this study was to develop a translational model of Cl 2 -induced ALI in swine to understand toxico-pathophysiology and evaluate whether it is suitable for screening potential medical countermeasures and to identify biomarkers useful for forensic analysis. Specific pathogen-free Yorkshire swine (30-40 kg) of either sex were exposed to Cl 2 (≤240 ppm for 1 h) or filtered air under anesthesia and controlled mechanical ventilation. Exposure to Cl 2 resulted in severe hypoxia and hypoxemia, increased airway resistance and peak inspiratory pressure, and decreased dynamic lung compliance. Cl 2 exposure resulted in increased total leucocyte and neutrophil counts in bronchoalveolar lavage fluid, vascular leakage, and pulmonary edema compared with the air-exposed group. The model recapitulated all three key histopathological features of human ALI, such as neutrophilic alveolitis, deposition of hyaline membranes, and formation of microthrombi. Free and lipid-bound 2-chlorofatty acids and chlorotyrosine-modified proteins (3-chloro-l-tyrosine and 3,5-dichloro-l-tyrosine) were detected in plasma and lung tissue after Cl 2 exposure. In this study, we developed a translational swine model that recapitulates key features of human Cl 2 inhalation injury and is suitable for testing medical countermeasures, and validated chlorinated fatty acids and protein adducts as biomarkers of Cl 2 inhalation. NEW & NOTEWORTHY We established a swine model of chlorine gas-induced acute lung injury that exhibits several features of human acute lung injury and is suitable for screening potential medical countermeasures. We validated chlorinated fatty acids and protein adducts in plasma and lung samples as forensic biomarkers of chlorine inhalation.

Exhaled breath (EB) contains various volatile organic compounds (VOCs) that can indicate specific biological or pathological processes in the body. Analytical techniques like gas chromatography-mass spectrometry (GC-MS) can be used to detect and measure these exhaled biomarkers. In this study, the objective was to develop a non-invasive method of EB sampling in animals that were awake, as well as to analyze EB for volatile biomarkers specific for chlorine exposure and/or diagnostic biomarkers for chlorine-induced acute lung injury (ALI). To achieve this, a custom-made sampling device was used to collect EB samples from 19 female Balb/c mice. EB was sampled both pre-exposure (serving as internal control) and 30 min after exposure to chlorine. EB was collected on thermal desorption tubes and subsequently analyzed for VOCs by GC-MS. The following day, the extent of airway injury was assessed in the animals by examining neutrophils in the bronchoalveolar lavage fluid. VOC analysis revealed alterations in the EB biomarker pattern post-chlorine exposure, with eight biomarkers displaying increased levels and six exhibiting decreased levels following exposure. Four chlorinated compounds: trichloromethane, chloroacetone, 1,1-dichloroacetone and dichloroacetonitrile, were increased in chlorine-exposed mice, suggesting their specificity as chlorine EB biomarkers. Furthermore, chlorine-exposed mice displayed a neutrophilic inflammatory response and body weight loss 24 h following exposure. In conclusion, all animals developed an airway inflammation characterized by neutrophil infiltration and a specific EB pattern that could be extracted after chlorine exposure. Monitoring EB samples can readily and non-invasively provide valuable information on biomarkers for diagnosis of chlorine-induced ALI, confirming chlorine exposures., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Chlorine (Cl 2 ) exposure poses a significant risk to ocular health, with the cornea being particularly susceptible to its corrosive effects. Antioxidants, known for their ability to neutralize reactive oxygen species (ROS) and alleviate oxidative stress, were explored as potential therapeutic agents to counteract chlorine-induced damage. In vitro experiments using human corneal epithelial cells showed decreased cell viability by chlorine-induced ROS production, which was reversed by antioxidant incubation. The mitochondrial membrane potential decreased due to both low and high doses of Cl 2 exposure; however, it was recovered through antioxidants. The wound scratch assay showed that antioxidants mitigated impaired wound healing after Cl 2 exposure. In vivo and ex vivo, after Cl 2 exposure, increased corneal fluorescein staining indicates damaged corneal epithelial and stromal layers of mice cornea. Likewise, Cl 2 exposure in human ex vivo corneas led to corneal injury characterized by epithelial fluorescein staining and epithelial erosion. However, antioxidants protected Cl 2 -induced damage. These results highlight the effects of Cl 2 on corneal cells using in vitro, ex vivo, and in vivo models while also underscoring the potential of antioxidants, such as vitamin A, vitamin C, resveratrol, and melatonin, as protective agents against acute chlorine toxicity-induced corneal injury. Further investigation is needed to confirm the antioxidants' capacity to alleviate oxidative stress and enhance the corneal healing process.

Inhaled toxicants are used for diverse purposes, ranging from industrial applications such as agriculture, sanitation, and fumigation to crowd control and chemical warfare, and acute exposure can induce lasting respiratory complications. The intentional release of chemical warfare agents (CWAs) during World War I caused life-long damage for survivors, and CWA use is outlawed by international treaties. However, in the past two decades, chemical warfare use has surged in the Middle East and Eastern Europe, with a shift toward lung toxicants. The potential use of industrial and agricultural chemicals in rogue activities is a major concern as they are often stored and transported near populated areas, where intentional or accidental release can cause severe injuries and fatalities. Despite laws and regulatory agencies that regulate use, storage, transport, emissions, and disposal, inhalational exposures continue to cause lasting lung injury. Industrial irritants (e.g., ammonia) aggravate the upper respiratory tract, causing pneumonitis, bronchoconstriction, and dyspnea. Irritant gases (e.g., acrolein, chloropicrin) affect epithelial barrier integrity and cause tissue damage through reactive intermediates or by direct adduction of cysteine-rich proteins. Symptoms of CWAs (e.g., chlorine gas, phosgene, sulfur mustard) progress from airway obstruction and pulmonary edema to acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), which results in respiratory depression days later. Emergency treatment is limited to supportive care using bronchodilators to control airway constriction and rescue with mechanical ventilation to improve gas exchange. Complications from acute exposure can promote obstructive lung disease and/or pulmonary fibrosis, which require long-term clinical care. SIGNIFICANCE STATEMENT: Inhaled chemical threats are of growing concern in both civilian and military settings, and there is an increased need to reduce acute lung injury and delayed clinical complications from exposures. This minireview highlights our current understanding of acute toxicity and pathophysiology of a select number of chemicals of concern. It discusses potential early-stage therapeutic development as well as challenges in developing countermeasures applicable for administration in mass casualty situations., (U.S. Government work not protected by U.S. copyright.)

Chlorine is a toxic industrial chemical that has been used as a chemical weapon in recent armed conflicts. Confirming human exposure to chlorine has proven challenging, and there is currently no established method for analyzing human biomedical samples to unambiguously verify chlorine exposure. In this study, two chlorine-specific biomarkers: palmitoyl-oleoyl phosphatidylglycerol chlorohydrin (POPG-HOCl) and the lipid derivative oleoyl ethanolamide chlorohydrin (OEA-HOCl) are shown in bronchoalveolar lavage fluid (BALF) samples from spontaneously breathing pigs after chlorine exposure. These biomarkers are formed by the chemical reaction of chlorine with unsaturated phospholipids found in the pulmonary surfactant, which is present at the gas-liquid interface within the lung alveoli. Our results strongly suggest that lipid chlorohydrins are promising candidate biomarkers in the development of a verification method for chlorine exposure. The establishment of verified methods capable of confirming the illicit use of toxic industrial chemicals is crucial for upholding the principles of the Chemical Weapons Convention (CWC) and enforcing the ban on chemical weapons. This study represents the first published dataset in BALF revealing chlorine biomarkers detected in a large animal. Furthermore, these biomarkers are distinct in that they originate from molecular chlorine rather than hypochlorous acid., 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., (Crown Copyright © 2023. Published by Elsevier B.V. All rights reserved.)

Characterization of the pathophysiology of ARDS following chlorine gas inhalation in clinically relevant translational large animal models is essential, as the opportunity for clinical trials in this type of trauma is extremely limited. To investigate Cl 2 concentration and gender-dependent ARDS severity. Sheep (n = 54) were exposed to air or Cl 2 premixed in air at a concentration of 50, 100, 200, and 300 ppm for 30 min under anesthesia/analgesia and monitored for an additional 48 h in a conscious state. Cardiopulmonary variables and survival endpoints were compared between male and female sheep. Overall there were no significant differences in the responses of female and male sheep except pulmonary oxygenation tended to be better in the male sheep (300 ppm group), and the pulmonary arterial pressure was lower (200 ppm group). The onset of mild ARDS (200 < PaO 2 /FiO 2  ≤ 300) was observed at 36 h post exposure in the 50 ppm group, whereas the 100 ppm group developed mild and moderate (100 ≤ PaO 2 /FiO 2  ≤ 200) ARDS by 12 and 36 h after injury, respectively. The 200 ppm and 300 ppm groups developed moderate ARDS within 6 and 3 h after injury, respectively. The 300 ppm group progressed to severe (PaO 2 /FiO 2  ≤ 100) ARDS at 18 h after injury. Increases in pPeak and pPlateau were noted in all injured animals. Compared to sham, inhalation of 200 ppm and 300 ppm Cl 2 significantly increased lung extravascular water content. The thoracic cavity fluid accumulation dose-dependently increased with the severity of trauma as compared to sham. At necropsy, the lungs were red, heavy, solidified, and fluid filled; the injury severity grew with increasing Cl 2 concentration. The severity of ARDS and mortality rate directly correlated to inhaled Cl 2 concentrations. No significant sex-dependent differences were found in measured endpoint variables., (© 2023. The Author(s).)

The objective of this study was to explore the effects of antioxidant treatments, specifically N-acetylcysteine (NAC) and N-acetylcysteine amide (NACA), in a mouse model of chlorine (Cl 2 )-induced lung injury. Additionally, the study aimed to investigate the utility of pig precision-cut lung slices (PCLS) as an ex vivo alternative for studying the short-term effects of Cl 2 exposure and evaluating antioxidant treatments. The toxicological responses were analyzed in Cl 2 -exposed mice (inflammation, airway hyperresponsiveness (AHR)) and PCLS (viability, cytotoxicity, inflammatory mediators). Airways contractions were assessed using a small ventilator for mice and electric-field stimulation (EFS) for PCLS. Antioxidant treatments were administered to evaluate their effects. In Cl 2 -exposed mice, NAC treatment did not alleviate AHR, but it did reduce the number of neutrophils in bronchoalveolar lavage fluid and inflammatory mediators in lung tissue. In PCLS, exposure to Cl 2 resulted in concentration-dependent toxicity, impairing the lung tissue's ability to respond to EFS-stimulation. NAC treatment increased viability, mitigated the toxic responses caused by Cl 2 exposure, and maintained contractility comparable to unexposed controls. Interestingly, NACA did not provide any additional treatment effect beyond NAC in both models. In conclusion, the establishment of a pig model for Cl 2 -induced lung damage supports further investigation of NAC as a potential treatment. However, the lack of protective effects on AHR after NAC treatment in mice suggests that NAC alone may not be sufficient as a complete treatment for Cl 2 injuries. Optimization of existing medications with a polypharmacy approach may be more successful in addressing the complex sequelae of Cl 2 -induced lung injury., 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 © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Chlorination is a widely used antifouling method for freshwater and marine applications. Chlorine added to seawater reacts to form oxidants that are toxic to biofouling organisms. Further, the oxidants that result are short-lived, but may nevertheless affect non-target species in waterbodies receiving the antifouling effluent. This study evaluated the toxicity of chlorinated seawater (e.g. following sodium hypochlorite addition) on two different species of marine benthic diatoms ( Achnanthes spp., and Navicula pelliculosa ), which are representative of microphytobenthos communities – an important component in coastal habitats that may be exposed to chlorinated seawater. To evaluate the growth inhibition over a 72 h period, algae were immobilised in alginate beads and exposed to different levels of chlorination in a flow through system. Growth rates and physiological condition of the microalgae were evaluated using a Fast Repetition Rate fluorometer (FRRf). To determine whether alginate influenced the sensitivity of algal response, studies were also conducted in a static test system (without renewal of test solutions) using both free cells and immobilised cells with initial chlorine added to achieve a similar range of concentrations as those used in the flow-through study. Within the first hour of the exposure period there was an indication that, for both species, the free algal cells in the static system were more sensitive to exposure to chlorinated seawater than were alginate-immobilised cells in the flow through system. Immobilised cells in a static system with a single addition of chlorine were also less sensitive to chlorination than free algal cells. However, for periods of 24 h or more due to decay of TRO in the static system the exposure of immobilised algae in the flow through system had a greater impact and hence lower effect concentrations. For the flow-through studies Achnanthes spp. was the most sensitive after 72 h exposure with a potential no effect concentration EC 10 value of 0.02 mg l −1 as Cl 2 equivalents expressed as total residual oxidants (TRO) compared 0.04 mg l −1 TRO for N. pelliculosa . Immobilisation of algal cells in alginate was found to be an effective means of determining the impact of chlorination and is likely to be effective for other non-persistent substances. Based on the data produced, the extent and significance of ecological effects of chlorination upon algal species typical of microphytobenthos are likely to be limited providing discharges comply with a maximum allowable concentration of 0.01 mg l −1 TRO at the edge of an agreed mixing zone. [ABSTRACT FROM AUTHOR]

Diethylamino hydroxybenzoyl hexyl benzoate (DHHB), an ultraviolet (UV) filter, can be found in sunscreens and other personal care products and thus can be introduced into swimming pools through the swimmers. In outdoor pools, DHHB will inevitably interact with free chlorine and sunlight. Therefore, the mechanism of solar‑chlorine chemical transformation of DHHB, as well as the environmental risk, were investigated in this work. In chlorinated with solar (Cl + solar) process, free chlorine was the dominant contributor to 85% of the DHHB degradation, while hydroxyl radicals and reactive chlorine species contributed only 15% because of low free radical generation and fast DHHB and free chlorine reaction rates. Scavenging matrices, such as Cl - , NH 4 + , and dissolved organic matter (DOM), inhibited the degradation of DHHB in the Cl + solar process, while Br - , HCO 3 - , NO 3 - , and urea promoted DHHB degradation. DHHB degradation was inhibited in tap water swimming pool samples, while it was enhanced in seawater pool samples by the Cl + solar process. Seven transformation by-products (TBPs) including mono-, dichlorinated, dealkylate, and monochloro-hydroxylated TBPs were identified. Three degradation pathways, chlorine substitution, chlorine and hydroxyl substitution, and dealkylation were proposed for DHHB transformation in the Cl + solar process. Both Quantitative structure-activity relationship and Aliivibrio fischeri toxicity tests demonstrated increased toxicity for the chlorinated TBPs. A risk assessment of the DHHB and its TBPs suggested that both DHHB and its chlorinated TBPs pose a significant health risk., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Rui Qin reports financial support was provided by Hainan Province Natural Science Foundation. Rui Qin reports financial support was provided by Hainan University. Shuai Dong reports financial support was provided by Hainan University. Zuo Tong How reports financial support was provided by National Natural Science Foundation of China., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Polychlorinated biphenyls (PCBs) with different chlorine substitution patterns often coexist in e-waste-processing sites. However, the single and combined toxicity of PCBs to soil organisms and the influence of chlorine substitution patterns remain largely unknown. Herein, we evaluated the distinct in vivo toxicity of PCB28 (a trichlorinated PCB), PCB52 (a tetrachlorinated PCB), PCB101 (a pentachlorinated PCB), and their mixture to earthworm Eisenia fetida in soil, and looked into the underlining mechanisms in an in vitro test using coelomocytes. After a 28-days exposure, all PCBs (up to 10 mg/kg) were not fatal to earthworms, but could induce intestinal histopathological changes and microbial community alterations in the drilosphere system, along with a significant weight loss. Notably, pentachlorinated PCBs with a low bioaccumulation ability showed greater inhibitory effects on the growth of earthworm than lowly chlorinated PCBs, suggesting that bioaccumulation was not the main determinant of chlorine substitution-dependent toxicity. Furthermore, in vitro assays showed that the highly chlorinated PCBs induced a high-percentage apoptosis of eleocytes in the coelomocytes and significantly activated antioxidant enzymes, indicating that the distinct cellular vulnerability to lowly/highly chlorinated PCBs was the main contributor to the PCBs toxicity. These findings emphasize the specific advantage of using earthworms in the control of lowly chlorinated PCBs in soil due to their high tolerance and accumulation ability., 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 article., (Copyright © 2022. Published by Elsevier B.V.)

Chlorine (Cl 2 ) is a disinfectant often used in swimming pools and water treatment facilities. However, it is released into aquatic ecosystems, where it may harm non-targeted organisms. Here, we performed a mesocosm experiment exposing Zacco platypus (Z. platypus) to biocide Cl 2 for 30 days (30 d) at two days' time points 15 days (15 d) and 30 d samples were collected. Here, Z. platypus was exposed to a sublethal concentration (0.1 mg/L) of Cl 2 , and comparative transcriptomics analyses were performed to determine their response mechanisms at the molecular level. According to RNA sequencing of the whole-body transcriptome, 860 and 1189 differentially expressed genes (DEGs) were identified from the 15 d and 30 d responses to Cl 2 , respectively. After enrichment analysis of GO (Gene Ontology) functions and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways, identified DEGs were demonstrated to be associated with a variety of functions, including "ion binding and transmembrane transporters". Cl 2 also induced oxidative stress in Z. platypus by increasing the levels of reactive oxygen species (ROS) while decreasing the catalase (CAT) content and the levels of solute carrier family 22 member 11 (slc22a11), Caspase-8 (casp-8), inducible nitric oxide synthase (NOS2), cytosolic phospholipase A2 gamma (PLA2G4). However, Z. platypus still allows recovery during stress suspension by increasing the expression levels of solute carrier family proteins. The GO and KEGG annotation results revealed that the expression of DEGs were related to the detoxification process, immune response, and antioxidant mechanism. Additionally, protein-protein interaction networks (PPI) and cytoHubba analyses identified sixteen hub genes and their interaction. These findings elucidate the regulation of various DEGs and signaling pathways in response to Cl 2 exposure, which will improve our knowledge and laid foundation for further investigation of the toxicity of Cl 2 to Z. platypus., 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 © 2023 Elsevier Ltd. All rights reserved.)

Chlorine (Cl 2 ) gas is a highly toxic and oxidizing irritant that causes life-threatening lung injuries. Herein, we investigated the impact of Cl 2 -induced injury and oxidative stress on lung macrophage phenotype and function. Spontaneously breathing male C57BL/6J mice were exposed to air or Cl 2 (300 ppm, 25 min) in a whole-body exposure chamber. Bronchoalveolar lavage (BAL) fluid and cells, and lung tissue were collected 24 h later and analyzed for markers of injury, oxidative stress and macrophage activation. Exposure of mice to Cl 2 resulted in increases in numbers of BAL cells and levels of IgM, total protein, and fibrinogen, indicating alveolar epithelial barrier dysfunction and inflammation. BAL levels of inflammatory proteins including surfactant protein (SP)-D, soluble receptor for glycation end product (sRAGE) and matrix metalloproteinase (MMP)-9 were also increased. Cl 2 inhalation resulted in upregulation of phospho-histone H2A.X, a marker of double-strand DNA breaks in the bronchiolar epithelium and alveolar cells; oxidative stress proteins, heme oxygenase (HO)-1 and catalase were also upregulated. Flow cytometric analysis of BAL cells revealed increases in proinflammatory macrophages following Cl 2 exposure, whereas numbers of resident and antiinflammatory macrophages were not altered. This was associated with increases in numbers of macrophages expressing cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS), markers of proinflammatory activation, with no effect on mannose receptor (MR) or Ym-1 expression, markers of antiinflammatory activation. Metabolic analysis of lung cells showed increases in glycolytic activity following Cl 2 exposure in line with proinflammatory macrophage activation. Mechanistic understanding of Cl 2 -induced injury will be useful in the identification of efficacious countermeasures for mitigating morbidity and mortality of this highly toxic gas., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Debra L Laskin reports financial support was provided by National Institutes of Health., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Hemodialysis uses municipal water that must be strictly purified and sterilized to be used for that procedure. Large amounts of decontaminants are often used, such as chlorine, and if these compounds are not subsequently removed they can be transferred to the blood of patients causing complications including methemoglobinemia., Methods: In this case series study, dialysis patients in one unit were evaluated. We reviewed clinical characteristics and laboratory findings obtained on the day when the water supply was disinfected with chlorine, with the aim to quantify methemoglobin concentrations. Our objective was to characterize the clinical presentation and management of patients who presented with methemoglobinemia on a specific index day. We also reviewed reported cases in the literature regarding this underreported complication., Results: Eight patients who presented with chlorine intoxication were evaluated. The methemoglobin concentrations were between 1.3% and 7.9% (reference value 0-1%). We believe this to be caused by water containing 0.78 mg/L of total chlorine. Seven patients presented with cyanosis, 4 with dizziness, 6 with dark brown blood, 4 with dyspnea, and 4 with headache and hemolytic anemia. Subjects were treated with supplemental oxygen, methylene blue, intravenous vitamin C, blood transfusions, and increased doses of erythropoietin. No patient died, and all continued with their usual hemodialysis sessions., Conclusion: Acute chlorine intoxication transferred by the water used during hemodialysis sessions can present with methemoglobinemia accompanied by cyanosis, oxygen desaturation, and hemolytic anemia. Chlorine levels should be carefully monitored in the water used for hemodialysis treatment., (© 2023 S. Karger AG, Basel.)

Chlorine (Cl 2 ) gas is a toxic industrial chemical (TIC) that poses a hazard to human health following accidental and/or intentional (e.g. terrorist) release. By using a murine model of sub-lethal Cl 2 exposure we have examined the airway hyper responsiveness, cellular infiltrates, transcriptomic and proteomic responses of the lung. In the "crisis" phase at 2 h and 6 h there is a significant decreases in leukocytes within bronchoalveolar lavage fluid accompanied by an upregulation within the proteome of immune pathways ultimately resulting in neutrophil influx at 24 h. A flip towards "repair" in the transcriptome and proteome occurs at 24 h, neutrophil influx and an associated drop in the lung function persisting until 14 d post-exposure and subsequent "recovery" after 28 days. Collectively, this research provides new insights into the mechanisms of damage, early global responses and processes of repair induced in the lung following the inhalation of Cl 2 ., (Crown Copyright © 2022. Published by Elsevier Inc. All rights reserved.)

Chlorine (reactive chlorine: Cl+OCl) is used as a disinfectant on prawn farms but the environmental effects of discharged chlorine is of environmental concern. Toxicity of chlorine on prawn farm phytoplankton populations was monitored using the pulse amplitude fluorometer technique to measure phytoplankton photosynthesis. The dominant phytoplankton species found in the ponds of a prawn farm in Pang-Nga Province (Thailand) were Chlorella sp. (>95 %), with some Tetraselmis and Chaetoceros. Cells were suspended in clean sea water with (chlorine) of 15, 30, 45, 60, 75 and 90 ppm, respectively, in short-term experiments for 10 min (ST) and for long-term (24 h) exposure. Photosynthesis of Chlorella, Tetraselmis and Chaetoceros in clean sea water was inhibited by 50 % at (chlorine) of 4.68 ± 0.6, 7.26 ± 1.14 and 7.81 ± 0.78 ppm (mean ± SEM), respectively, in ST experiments. The chlorine consuming reactions with the large amounts of dissolved organic matter and ammonia in prawn farm pond water decreases toxicity but would form organochlorines and chloramine. Thiosulphate, often used to neutralise chlorine, was found to be of very limited toxicity to Chlorella in both short-term 1-h and 24-h experiments (up to ≈500 mmol m, 124 ppm). Environmental effects of Chlorine in discharges from ponds are short term. Chlorine quickly disappears in the environment, particularly during daylight and so only has effects close to effluent points. Standard practice was to discharge on a falling tide in daylight. The long effluent channel (1 km) also ensured that very little reactive chlorine reached the estuary. [ABSTRACT FROM AUTHOR]

Azithromycin (AZM), an antibacterial considered one of the most consumed drugs, especially during the period against the Covid 19 pandemic, and it is one of the persistent contaminants that can be released into aquatic ecosystems. The purpose of this study is to determine the efficacy of a Fenton-like process (chlorine/iron) for the degradation of AZM in an aqueous medium by determining the impact of several factors (the initial concentration of (FeSO 4 , NaClO, pollutant), and the initial pH) on the degradation rate. The Response Surface Methodology (RSM) based on the Box-Wilson design as well as the Artificial Neural Network (ANN) modeling combined with a genetic algorithm (GA) approaches were used to determine the optimal levels of the selected variables and the optimal rate of degradation. The quadratic model of multi-linear regression developed indicated that the optimal conditions were a concentration of chlorine of 600 μM, the concentration of AZM is 32.8 mg/L, the mass of the catalyst FeSO 4 is 3.5 mg and a pH of 2.5, these optimal values gave a predicted and experimental yield of 64.05% and 70% respectively, the lack of fit test in RSM modeling (F 0  = 3.31 which is inferior to Fcritic (0.05, 10.4) = 5.96) indicates that the true regression function is not linear therefore, the ANN-GA modeling as non-linear regression indicated that the optimal conditions were a concentration of chlorine of 256 μM, the concentration of AZM is 5 mg/L, the mass of the catalyst FeSO 4 is 9.5 mg and a pH of 2.8, these optimal values gave a predicted and experimental yield of 79.69% and close to 80% respectively, Furthermore, biotoxicity tests were conducted to confirm the performance of our process using bio-indicators called daphnia (Daphnia magna), which demonstrated the efficacy of the like-Fenton process after 4 h of degradation., 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 © 2022 Elsevier Inc. All rights reserved.)

Rationale: Exercise-induced bronchoconstriction (EIB) is defined as acute narrowing of the airways during or immediately after exercise. EIB has a high prevalence in elite swimmers probably due to the high ventilation rate and exposure to the chlorine by-products. It is still puzzling which pathophysiological mechanisms drive EIB., Objective: In this study, we evaluated airway hyperreactivity, permeability, integrity and inflammation in a murine swimmers EIB model with and without chlorine exposure., Methods: Mice performed a 3-week swimming protocol in a swimming pool with counter current. Three hours after the last swimming session, airway hyperreactivity to methacholine was assessed. Cytokine levels and cellular differential analysis was performed in BAL fluid. Airway permeability and tight junction expression was measured in serum and lung tissue. T-, B-, dendritic and innate lymphoid cells were determined in lung tissue via flow cytometry., Results: A significant higher airway resistance (Rn; P < 0.0001) was observed in mice swimming in chlorinated water (mean Rn = 1.26 cmH 2 O.s/ml) compared to mice swimming in tap water (mean Rn = 0.76 cmH 2 O.s/ml) and both inhalation groups in the absence of cellular inflammation. No significant differences were found in lung immune cell populations or in lung tight junction mRNA expression. Experiments in SCID, Rag2 -/- γc -/- or Cpa3 cre/+ mice showed a limited involvement of the innate, adaptive immune system or the mast cells., Conclusion: Our 3-week swimming murine model mimics intensive swimming in chlorinated water with the presence of airway hyperreactivity in mice swimming in chlorinated water in the absence of airway inflammation and airway epithelial damage., 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 © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Pistachio trees have been cultivated on the island of Aegina, Greece, since 1860. The dominant variety Aegina is one of the finest pistachio varieties in the world. The aim of the study was to collect some information on the inorganic nutrition of pistachio in the area for fertilization recommendations to be more appropriate. Additionally, the causes of two types of symptoms observed in some orchards during summer have been investigated. The first one concerned severe burning or scorching on the tips or edges of the leaves, and the other concerned small, narrow leaves bunched together at the tips of the shoots. Thus, in the first days of August, fully expanded subterminal leaflets from nonfruiting branches from 41 commercial orchards, consisting of pistachio trees var. Aegina grafted ontoPistacia terebinthuscv. Tsikoudia, were collected and chemically analyzed. The results showed that 54% of pistachio orchards presented leaf nitrogen concentration below the critical value; the percentages were 20% in the case of phosphorus and 22% in the case of potassium. Calcium level was within the normal range in all orchards, whereas leaf chlorine was excessive in some cases. With regard to micronutrients iron, manganese and boron, levels were within the normal ranges, 30–50 ppm, 20–80 ppm, and 100–200 ppm, respectively, but zinc was below the critical value in 51% of the orchards tested. As for the symptoms observed, the first type of symptoms should be related to low potassium and/or excessive chloride concentration, whereas the second one should be related to zinc deficiency. [ABSTRACT FROM AUTHOR]

1,3-diphenylguanidine (DPG) is a commonly used rubber and polymer additive, that has been found to be one of the main leachate products of tire wear particles and from HDPE pipes. Its introduction to aquatic environments and potentially water supplies lead to further questions regarding the effects of disinfection by-products potentially formed. Using different bioassay approaches and NGS RNA-sequencing, we show that some of the chlorinated by-products of DPG exert significant toxicity. DPG and its chlorinated by-products also can alter cell bioenergetic processes, affecting cellular basal respiration rates and ATP production, moreover, DPG and its two chlorination products, 1,3-bis-(4-chlorophenyl)guanidine (CC04) and 1-(4-chlorophenyl)-3-(2,4-dichlorophenyl)guanidine (CC11), have an impact on mitochondrial proton leak, which is an indicator of mitochondria damage. Evidence of genotoxic effects in the form of DNA double strand breaks (DSBs) was suggested by RNA-sequencing results and further validated by an increased expression of genes associated with DNA damage response (DDR), specifically the canonical non-homologous end joining (c-NHEJ) pathway, as determined by qPCR analysis of different pathway specific genes (XRCC6, PRKDC, LIG4 and XRCC4). Immunofluorescence analysis of phosphorylated histone H2AX, another DSB biomarker, also confirmed the potential genotoxic effects observed for the chlorinated products. In addition, chlorination of DPG leads to the formation of different chlorinated products (CC04, CC05 and CC15), with analysed compounds representing up to 42% of formed products, monochloramine is not able to effectively react with DPG. These findings indicate that DPG reaction with free chlorine doses commonly applied during drinking water treatment or in water distribution networks (0.2-0.5 mg/L) can lead to the formation of toxic and genotoxic chlorinated products., (Copyright © 2022. Published by Elsevier B.V.)

Chlorinated disinfection byproducts in water posed potential health threat to humans. Nowadays, chlorinated derivatives of diazepam were ubiquitously detected in drinking water. Among these derivatives, 2-methylamino-5-chlorobenzophenone (MACB) was capable of penetrating the blood-brain barrier (BBB) and induced microglial phagocytosis of neurons in zebrafish. However, little is known about the MACB metabolism in vivo. Here, we determined the metabolism of MACB in zebrafish and microglia cell model. We found that MACB mainly disrupted the metabolism of branched-chain amino acids (Leu, Ile and Val) in zebrafish model and gamma-aminobutyric acid (GABA) pathway-related amino acids in microglia model. Additionally, we demonstrated that MACB can be metabolized by the mixed-function oxidase CYP1A2 enzyme which could be inhibited by estrogen causing the gender-difference in the accumulation of MACB in vivo. These results indicated that MACB perturbed metabolism and induced neurological disorders, particularly in the female zebrafish., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Calcium hypochlorite is a yellow-white powder widely used as a disinfectant in swimming pools. It releases chlorine gas when added to water and can cause respiratory effects. Dermal and eye injury can occur because of the caustic nature of chlorine. We report a case of chlorine toxicity and burns on a man’s face due to the explosion of calcium hypochlorite while he was mixing it into the water. [ABSTRACT FROM AUTHOR]

The quality of the water supplied to Araraquara city (São Paulo State, Brazil) was analyzed at four points: two reservoirs from which water is pumped and the water incoming and exiting a drinking- water treatment plant. Physical and chemical analyses of water were performed, as well as acute and chronic toxicity tests of the water from all four points, using Ceriodaphnia silvestrii (Cladocera, Crustacea) as test-organism. The study was carried out monthly in the period between December 2000 and November 2001. Water from the reservoirs caused neither acute nor chronic toxicity to test-organisms. On the contrary, it promoted an increase in the fecundity of cladocerans compared to control, suggesting greater availability of food. However, the water from exiting the treatment plant did cause chronic toxicity to C. silvestrii, regarding both fecundity and mortality. The toxicity was probably caused by residual chlorine, perhaps not completely removed by aeration, or by chlorine disinfection by-products (trihalomethanes) in the treated water, considering the level of organic matter present in the reservoir water. [ABSTRACT FROM AUTHOR]

Chlorine (Cl 2 ) is a common toxic industrial gas and human inhalation exposure causes tissue damage with symptoms ranging from wheezing to more severe symptoms such as lung injury or even death. Because the mechanism behind Cl 2 -induced cell death is not clearly understood, the present study aimed to study the cellular effects in vitro after Cl 2 exposure of human A549 lung epithelial cells. In addition, the possible treatment effects of the anti-inflammatory antioxidant N-acetyl cysteine (NAC) were evaluated. Exposure of A549 cells to Cl 2 (100-1000 ppm) in the cell medium induced cell damage and toxicity within 1 h in a dose-dependent manner. The results showed that 250 ppm Cl 2 increased cell death and formation of apoptotic-like bodies, while 500 ppm Cl 2 exposure resulted in predominantly necrotic death. Pre-treatment with NAC was efficient to prevent cell damage at lower Cl 2 concentrations in part by averting the formation of apoptotic-like bodies and increasing the expression of the anti-apoptotic proteins clusterin and phosphorylated tumour protein p53(S46). Analysis showed that Cl 2 induced cell death by a possibly caspase-independent mechanism, since no cleavage of caspase-3 could be detected after exposure to 250 ppm. Currently, these results justifies further research into new treatment strategies for Cl 2 -induced lung injury., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Tannic acid is ubiquitously present in various simulated and real water sources and in wastewater. Various chlorinated disinfection byproducts (Cl-DBPs) are generated via reactions with tannic acid during disinfection with chlorine. We used high-resolution mass spectrometry in combination with our self-developed halogen extraction code to selectively identify Cl-DBPs. Our strategy enabled successful detection of 35 Cl-DBP formulas formed by chlorination of tannic acid, and we identified 26 of these structures. The structures of 17 novel Cl-DBPs are firstly reported here. The reaction pathways of these Cl-DBPs were tentatively proposed. These Cl-DBPs are likely to be generated during chlorination at various chlorine doses, from 0.0 to 10.0 mg-Cl 2 /L, and 14 of the 26 Cl-DBPs were detected in simulated drinking water, which implies a relatively high probability of incidence. Quantitative structure-activity relationship toxicity analyses predicted that most of these Cl-DBPs would exhibit much higher acute toxicity than the common DBPs trichloromethane and monochloroacetic acid and that some of these compounds would induce developmental toxicity and be mutagenic, which further emphasizes that these Cl-DBPs should raise concerns. This study broadens our understanding of the Cl-DBPs formed from tannic acid and should prompt wider application of our analytical strategy in environmental matrices., (Copyright © 2021. Published by Elsevier B.V.)

Microplastics (MPs) are ubiquitous in drinking water and pose potential threats to human health. Despite increasingly attentions on the toxicity of MPs, the deleterious effects of MPs after chlorine disinfection, which might be a more accessible form of MPs, has rarely been considered. Here, we first treated pristine polystyrene microplastics (PS-MPs) with chlorine to simulate the reactions that occur during drinking water treatment, and investigated and compared the cytotoxicity of chlorinated PS-MPs to those of pristine PS-MPs. Chlorine disinfection did not change the size of pristine PS-MPs, but increased the surface roughness. In addition, abundant carbon-chlorine bonds and persistent free radicals were generated on the surface of chlorinated PS-MPs. Compared with pristine PS-MPs, chlorinated PS-MPs markedly inhibited the cell proliferation, changed cellular morphology, destroyed cell membrane integrity, induced cell inflammatory response and apoptosis. Proteomics confirmed the difference in interactions with intracellular proteins between these particles. Furthermore, we found that the regulation of PI3K/AKT and Bcl-2/Bax pathways, oxidative stress-triggered mitochondrial depolarization, and the activation of caspase cascade were identified as the underlying mechanisms for the enhanced apoptosis ratio in GES-1 cells when exposed to chlorinated PS-MPs. This exacerbated cytotoxicity could be explained by the enhanced surface roughness and changed surface chemistry of these PS-MPs after chlorine disinfection. This work discloses the impacts of chlorine disinfection on the cytotoxicity of PS-MPs, which provides new insights for a more systematic risk assessment of MPs., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Chlorine disinfection is a key global public health strategy for the prevention and control of diseases, such as COVID-19. However, little is known about effects of low levels of residual chlorine on freshwater microbial communities and antibiotic resistomes. Here, we treated freshwater microcosms with continuous low concentrations of chlorine and quantified the effects on aquatic and zebrafish intestinal microbial communities and antibiotic resistomes, using shotgun metagenome and 16S rRNA gene sequencing. Although chlorine rapidly degraded, it altered the aquatic microbial community composition over time and disrupted interactions among microbes, leading to decreases in community complexity and stability. However, community diversity was unaffected. The majority of ecological functions, particularly metabolic capacities, recovered after treatment with chlorine for 14 d, due to microbial community redundancy. There were also increased levels of antibiotic-resistance gene dissemination by horizontal and vertical gene transfer under chlorine treatment. Although the zebrafish intestinal microbial community recovered from temporary dysbiosis, growth and behavior of zebrafish adults were negatively affected by chlorine. Overall, our findings demonstrate the negative effects of residual chlorine on freshwater ecosystems and highlight a possible long-term risk to public health., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Heparan sulfate (HS) degradation mediates pulmonary endothelial hyper-permeability and acute pulmonary edema during acute respiratory distress syndrome (ARDS). The aim of this study was to examine whether histone H4 induced HS degradation by activating heparanase (HPSE) in chlorine gas (Cl 2 )-induced ARDS., Methods: Acute lung injury was induced by Cl 2 exposure or histone H4 injection in C57BL/6 mice. Histone H4 in bronchoalveolar lavage fluid (BALF) and plasma was measured by ELISA. HS degradation was measured by immunostaining, ELISA, and flow cytometry. HPSE mRNA and protein were measured by real-time qPCR and western blot analysis, respectively, at preset timepoints. The HPSE inhibitor OGT2115 and specific siRNAs were used to study the role of HPSE during HS degradation caused by Cl 2 exposure or histone H4 challenge. Blocking antibodies against TLR1, TLR2, TLR4, or TLR6 were used in vitro to investigate which signaling pathway was involved. The transcriptional regulation of HPSE was studied vis-à-vis NF-κB, which was assessed by nuclear translocation of NF-κB p65 and phosphorylation of I-κBα protein., Results: Histone H4 in BALF and plasma increased evidently after Cl 2 inhalation. Cl 2 exposure or histone H4 challenge caused obvious acute lung injury in mice, and the pulmonary glycocalyx was degraded evidently as observed from endothelial HS staining and measurement of plasma HS fragments. Pretreatment with OGT2115, an HPSE inhibitor, relieved the acute lung injury and HS degradation caused by Cl 2 exposure or histone H4 challenge. Targeted knockdown of HPSE by RNA interference (RNAi) significantly inhibited histone H4 induced HS degradation in HPMECs, as measured by immunofluorescence and flow cytometry. By inducing phosphorylation of I-κB α and nuclear translocation of NF-κB p65, histone H4 directly promoted mRNA transcription and protein expression of HPSE in a dose-dependent manner. Additionally, a blocking antibody against TLR4 markedly inhibited both activation of NF-κB and expression of HPSE induced by histone H4., Conclusions: Histone H4 is a major pro-inflammatory mediator in Cl 2 -induced ARDS in mice, and induces HS degradation by activating HPSE via TLRs- and NF-κB-signaling pathways., (© 2022. The Author(s).)

Resuscitation and detection of stressed total coliforms in chlorinated water samples is needed to assess and prevent health effects from adverse exposure. In this study, we report that the addition of a growth enhancer mix consisting of trehalose, sodium pyruvate, magnesium chloride, and 1× trace mineral supplement improved growth of microorganisms from chlorinated secondary effluent in the base medium with Colilert-18. Improving growth of chlorine stressed microorganisms from secondary effluent is crucial to decreased detection time from 18 to 8 h., (Copyright © 2021. Published by Elsevier B.V.)

Objective: Chlorine (Cl 2 ), as an asphyxiant toxicant, induced poisoning incidents and acute lung injury (ALI) occur frequently. The specific pathogenesis of Cl 2 -induced ALI remains unclear. Immune cells play an important role in the process of lung damage. We used single-cell RNA sequencing (scRNA-seq) technology to explore T cells and macrophages molecular mechanism., Methods: Female BALB/c mice were exposed to 400 ppm Cl 2 for 15 min. scRNA-seq technology was used to observe the heterogeneity of T cells and macrophages. Hematoxylin-eosin (H&E) staining was used to evaluate the degree of lung injury. Immunofluorescence was used to verify the highly expressed genes of our interest., Results: A total of 5316 to 7742 cells were classified into eight different cell types. Several new highly expressed anti-inflammatory and pro-inflammatory genes were found in T cells and macrophages, which were further verified in vitro. Through the pseudotime analysis of macrophages, it was found that the expression of pro-inflammatory and anti-inflammatory genes showed opposite trends in the development of Cl 2 -induced ALI. This study also mapped T cells-macrophage communication and identified the development of several important receptor-ligand complexes in Cl 2 -induced ALI., Conclusions: These findings are worthy of further exploration and provide new resources and directions for the study of Cl 2 -induced ALI in mice, especially in immune and inflammation mechanisms.

We assessed the effects of dexamethasone on functional and histological changes after acute exposure to a high level of chlorine gas in an animal model of reactive airways dysfunction syndrome (RADS). Sprague-Dawley male rats were exposed to 1500 ppm of chlorine for 5 min and treated with either dexamethasone (dex; 300 μg/kg/day) or saline intraperitoneally for 7 days. Lung resistance (RL), airway responsiveness to inhaled methacholine (MCh), airway wall morphometric measurements, and bronchoalveolar lavage (BAL) cells were assessed over a 2-week period after exposure. Dex administration significantly attenuated both chlorine-induced increased RL, and chlorine-induced increased responsiveness to methacholine compared with saline: −2.7 ± 6.8% vs 102.3 ± 36.6% change from baseline RL (P < 0.01) and 2.5 ± 0.6 mg/ml vs 1.2 ± 0.7 mg/ml in the MCh concentration required to double the RL from baseline (P < 0.01). There was a tendency, albeit nonsignificant, for improvement in some indices of epithelial injury. Dex significantly attenuated the postexposure neutrophilic cellular response in BAL 1 day after exposure (15.8 ± 4.9% neutrophils in the dex group vs 49.8 ± 2.7% neutrophils in the saline group) (P 5≤0.001). Our results show that dex administration helps maintain pulmonary function, reduces BAL inflammatory cell number, and tends to improve some morphometric airway wall structure parameters in rats exposed to chlorine. [ABSTRACT FROM PUBLISHER]

The halogens chlorine (Cl 2 ) and bromine (Br 2 ) are highly reactive oxidizing elements with widespread industrial applications and a history of development and use as chemical weapons. When inhaled, depending on the dose and duration of exposure, they cause acute and chronic injury to both the lungs and systemic organs that may result in the development of chronic changes (such as fibrosis) and death from cardiopulmonary failure. A number of conditions, such as viral infections, coexposure to other toxic gases, and pregnancy increase susceptibility to halogens significantly. Herein we review their danger to public health, their mechanisms of action, and the development of pharmacological agents that when administered post-exposure decrease morbidity and mortality.

Context: Bisphenol A (BPA) is a ubiquitous contaminant with endocrine-disrupting effects in mammals. During chlorination treatment of drinking water, aqueous BPA can react with chlorine to form chlorinated derivatives of BPA (mono, di, tri and tetra-chlorinated derivatives) or Cl x BPA., Objective: The aim of this study is to summarize and present the state of knowledge on human toxicological risk assessment of Cl x BPA., Materials and Methods: A search on Cl x BPA in the PubMed database was performed based on studies published between 2002 and 2021. Forty-nine studies on chlorinated derivatives of BPA were found. Available information on their sources and levels of exposure, their effects, their possible mechanisms of action and their toxicokinetics data was extracted and presented., Results: Cl x BPA have been essentially detected in environmental aqueous media. There is evidence in toxicological and epidemiological studies that Cl x BPA also have endocrine-disrupting capabilities. These emerging pollutants have been found in human urine, serum, breast milk, adipose and placental tissue and can constitute a risk to human health. However, in vitro and in vivo toxicokinetic data on Cl x BPA are scarce and do not allow characterization of the disposition kinetics of these compounds., Conclusion: More research to assess their health risks, specifically in vulnerable populations, is needed. Some water chlorination processes are particularly hazardous, and it is important to evaluate their chlorination by-products from a public health perspective., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Levofloxacin (LEV) is a broad-spectrum quinolone antibiotic and widely used for human and veterinary treatment. Overuse of LEV leads to its frequent occurrence in the water environment. In this study, the transformation characteristics of LEV in water during the simulated chlorination disinfection treatment were explored. Fifteen major transformation products (TPs) of LEV were identified, and their plausible formation pathways were proposed. The reaction pathways were strongly dependent on pH condition, and LEV removal was relevant to free available chlorine (FAC) dose. Antibacterial activity of chlorination system was dramatically declined when FAC was more than 3-equivalent (eq) due to the elimination of antibacterial related functional groups. Genotoxicity of chlorination system increased more than 3 times at 0.5-eq of FAC and then decreased with increasing FAC dose, which were in accordance with the relative concentration of toxic TPs estimated by QSAR model. These results implied that the combination of bioassay, QSAR computation and chemical analysis would be an efficient method to screen toxic TPs under chlorination treatment. It is anticipated that the results of this study can provide reference for optimizing operational parameters for water disinfection treatment, and for scientifically evaluating the potential risk of quinolone antibiotics., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Chlorine is a toxic industrial chemical produced in vast quantities globally, being used in a range of applications such as water purification, sanitation and industrial processes. Its use and transport cannot be restricted; exposure may occur following accidental or deliberate releases. The OPCW recently verified the use of chlorine gas against civilians in both Syria and Iraq. Chlorine inhalation produces damage to the lungs, which may result in the development of an acute lung injury, respiratory failure and death. Treatment remains an intractable problem. Our objective was to develop a clinically relevant pre-clinical model of a moderate to severe lung injury in the pig. This would enable future assessment of therapeutic drugs or interventions to be implemented in the pre-hospital phase after exposure. Due to the irritant nature of chlorine, a number of strategies for exposing terminally anesthetized pigs needed to be investigated. A number of challenges (inconsistent acute changes in respiratory parameters; early deaths), resulted in a moderate to severe lung injury not being achieved. However, most pigs developed a mild lung injury by 12 h. Further investigation is required to optimize the model and enable the assessment of therapeutic candidates. In this paper we describe the exposure strategies used and discuss the challenges encountered in establishing a model of chlorine-induced lung injury. A key aim is to assist researchers navigating the challenges of producing a clinically relevant model of higher dose chlorine exposure where animal welfare is protected by use of terminal anesthesia.

Chlorine gas is one of the highly produced chemicals in the USA and around the world. Chlorine gas has several uses in water purification, sanitation, and industrial applications; however, it is a toxic inhalation hazard agent. Inhalation of chlorine gas, based on the concentration and duration of the exposure, causes a spectrum of symptoms, including but not limited to lacrimation, rhinorrhea, bronchospasm, cough, dyspnea, acute lung injury, death, and survivors develop signs of pulmonary fibrosis and reactive airway disease. Despite the use of chlorine gas as a chemical warfare agent since World War I and its known potential as an industrial hazard, there is no specific antidote. The resurgence of the use of chlorine gas as a chemical warfare agent in recent years has brought speculation of its use as weapons of mass destruction. Therefore, developing antidotes for chlorine gas-induced lung injuries remains the need of the hour. While some of the pre-clinical studies have made substantial progress in the understanding of chlorine gas-induced pulmonary pathophysiology and identifying potential medical countermeasure(s), yet none of the drug candidates are approved by the U.S. Food and Drug Administration (FDA). In this review, we summarized pathophysiology of chlorine gas-induced pulmonary injuries, pre-clinical animal models, development of a pipeline of potential medical countermeasures under FDA animal rule, and future directions for the development of antidotes for chlorine gas-induced lung injuries.

Benzothiazole (BZA) and benzotriazole (BTZ) as emerging contaminants were found persistent in aquatic environments and toxic to aquatic organisms. The degradation of BZA and BTZ by UV/chlorine was systematically investigated in this study, and the results showed that BZA and BTZ can be remarkably removed by UV/chlorine compared with UV alone and dark chlorination. The radical quenching tests showed that degradation of BZA and BTZ by UV/chlorine involved the participation of reactive chlorine species (RCS), hydroxyl radical (HO·), and UV photolysis. HO· dominated BZA degradation at neutral and alkalinity, while RCS dominated BTZ degradation. The second-rate order constants for ClO· and BZA and BTZ were 2.22 × 10 8  M -1  s -1 , and 2.40 × 10 8  M -1  s -1 , respectively. Besides, the second-order rate constants for HO· and BZA and BTZ were also determined at pH 5.0, 7.0, and 9.0, respectively. The degradation efficiency of BZA by UV/chlorine was substantially promoted at acidic conditions, while the degradation efficiency of BTZ was promoted at both acidic and specific alkaline range mainly due to the reactivity of radical species and deprotonated form. The influence of Cl - was negligible, but the suppression effect of humic acid was slight during the BZA and BZT degradation by UV/chlorine. The transformation products were detected and the possible pathways were proposed. Seven disinfection by-products (DBPs) were identified both in BZA and BTZ degradation and trichloromethane was the main DBP. The toxicity assessment performed by luminescent bacteria and ECOSAR analysis indicated that the detoxification of BZA could be achieved by UV/chlorine, whereas the toxicity of BTZ was increased mainly due to the formation of intermediates. The findings from this study demonstrated UV/chlorine is likewise efficient for BZA and BTZ removal but the toxicity should be considered in the BTZ degradation., 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 © 2020. Published by Elsevier B.V.)

Objective: The main objective was to study different clinical presentations and outcomes of patients after acute industrial chlorine gas exposure in Oman with evaluation of overall incident management to help develop a chemical exposure incident protocol., Methods: This was a retrospective observational study of 15 patients exposed to chlorine gas after an accidental chlorine gas leak in a metal melting factory in Oman., Results: Six (40%) patients were admitted and nine (60%) patients were discharged from the emergency department (ED) after initial management. The important post-chlorine gas exposure clinical symptoms were eye irritation (66.6%), cough (73.3%), shortness of breath (40.0%), chest discomfort (66.6%), rhinorrhea (66.6%), dizziness (40.0%), vomiting (46.6%), sore throat (13.3%), and stridor (53.3%). Important signs included tachycardia (40.0%), tachypnea (40.0%), wheeze (20.0%), and use of accessory muscles for breathing (20.0%). Signs and symptoms of eye irritation, rhinorrhea, tachycardia, tachypnea, wheeze, and use of accessory muscles for breathing have shown significant correlation with outcome (admission) having P value of <.05., Conclusion: In the presented acute chlorine gas exposure incidence, 15 exposed persons were brought to the ED, out of which six were admitted and nine were discharged after symptomatic treatment. Signs and symptoms of eye irritation, rhinorrhea, tachycardia, tachypnea, wheeze, and use of accessory muscles of breathing show significant relation with the outcome of admission.

Combined UV-chlorine treatment is a promising disinfection technology providing synergistic effects on bacteria-killing. The interaction between UV and chlorine would affect pollutants removal and disinfection by-products formation, while little is known about how UV and chlorine respectively contribute to pollutants transformation under combined UV-chlorine treatment. In this study, UV filter 2,3,4-trihydroxybenzophenone (2,3,4-THBP) was selected as a model compound to investigate the transformation characteristics and acute toxicity variation under combined UV-chlorine treatment. Especially, separative UV and chlorination treatments were conducted to illustrate their respective contribution in combined UV-chlorine treatment. It was found that the optimal removal percentage of 2,3,4-THBP under combined UV-chlorine treatment was 85.3% within 5 min and kept stable until 3 h at 3-equivalent (equiv.) of free available chlorine (FAC) and 1 mW/cm 2 of irradiation intensity. Correspondingly, acute toxicity of reaction mixture at 3 h increased twice as high as that of 2,3,4-THBP itself. Four transformation products were tentatively identified, and their formation possibly involved the reactions of chlorine substitution, oxidation, hydroxylation, and hydrolysis. FAC initiated the preliminary transformation of 2,3,4-THBP, and the synergistic effects of UV and chlorine promoted the further transformation of intermediates from chlorination treatment. Most important was that, 2,3,4-THBP could form some toxic products in the real ambient water matrix under solar irradiation, and acute toxicity of reaction mixture was 1.84 times higher than that of 2,3,4-THBP. This study would provide a better understanding on the transformation characteristics of pollutants under combined UV-chlorine treatment, and provide a reference for optimizing disinfection treatment., 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 © 2020 Elsevier Ltd. All rights reserved.)

Chlorine (Cl 2 ) and bromine (Br 2 ) are produced in large quantities throughout the world and used in the industry and the sanitation of water. These halogens can pose a significant threat to public health when released into the atmosphere during transportation and industrial accidents, or as acts of terrorism. In this review, we discuss the evidence showing that the activity of Cl 2 and Br 2 , and of products formed by their interaction with biomolecules, fragment high-molecular-weight hyaluronan (HMW-HA), a key component of the interstitial space and present in epithelial cells, to form proinflammatory, low-molecular-weight hyaluronan fragments that increase intracellular calcium (Ca 2+ ) and activate RAS homolog family member A (RhoA) in airway smooth muscle and epithelial and microvascular cells. These changes result in airway hyperresponsiveness (AHR) to methacholine and increase epithelial and microvascular permeability. The increase in intracellular Ca 2+ is the result of the activation of the calcium-sensing receptor by Cl 2 , Br 2 , and their by-products. Posthalogen administration of a commercially available form of HMW-HA to mice and to airway cells in vitro reverses the increase of Ca 2+ and the activation of RhoA, and restores AHR to near-normal levels of airway function. These data have established the potential of HMW-HA to be a countermeasure against Cl 2 and Br 2 toxicity., (© 2020 New York Academy of Sciences.)

Exposure of mice to high concentrations of chlorine leads to the synthesis of cysteinyl leukotrienes (cysLTs). CysLTs contribute to chlorine-induced airway hyperresponsiveness. The aim of the current study was to determine the cellular source of the cysLTs. To achieve this aim, we exposed mice to 100 ppm of chlorine for 5 minutes. Intranasal instillation of clodronate in liposomes and of diphtheria toxin in CD11c-DTR mice was used to deplete macrophages. CCR2 -/- mice were used to assess the contribution of recruited macrophages. Eosinophils and neutrophils were depleted with specific antibodies. Platelet-neutrophil aggregation was prevented with an antibody against P-selectin. The potential roles of phagocytosis of neutrophils by macrophages and of transcellular metabolism between epithelial cells and neutrophils were explored in coculture systems. We found that depletion of neutrophils was the only intervention that inhibited the synthesis of cysLTs at 24 hours after chlorine exposure. Although macrophages did synthesize cysLTs in response to phagocytosis of neutrophils, depletion of macrophages did not reduce the increment in cysLTs triggered by chlorine exposure. However, coculture of airway epithelial cells with neutrophils resulted in a significant increase in the synthesis of cysLTs, dependent on the expression of 5-lipoxygenase by neutrophils. We conclude that cysLT synthesis following chlorine exposure may be dependent on transcellular metabolism by neutrophil-epithelial interactions.

Freshwater ecosystems are vulnerable to residual concentrations of chemical agents from anthropogenic activities, and the real impacts of such compounds can only be evaluated accurately using ecotoxicological tests. The assessment of ecotoxicological effects of peracetic acid (PAA) and the active chlorine of calcium hypochlorite (Ca(ClO) 2 ) on the insect Chironomus xanthus Meigen (Diptera: Chironomidae) is highly relevant as there are few reports on its effects in fresh water ecosystems. To our best knowledge, this is the first study to assess the chronic toxicity of the compounds to C. xanthus. The toxicity bioassays for C. xanthus included the acute effect (CL 50 ) and the chronic effects based on body length, head width, and cumulative emergence. The results obtained in the acute effect tests indicated that the active chlorine of Ca(ClO) 2 is 14 fold more toxic than PAA to C. xanthus. In sublethal evaluations, the active chlorine of Ca(ClO) 2 presented higher toxicity than PAA in terms of percentage emergence, body development, and head width. In general, the results showed lower PAA toxicity relative to the active chlorine of Ca(ClO) 2 , demonstrating that PAA is a promising substitute for chlorinated disinfectants. In addition, the study facilitates the establishment of reference values for the safe release of effluents treated with PAA into water bodies., 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 © 2020 Elsevier Ltd. All rights reserved.)

Lysosomes with a single-layered membrane structure are mainly involved in the scavenging of foreign substances and play an important role in maintaining normal physiological functions of living cells. In this work, near-neutrally charged fluorescent carbon dots (CDs) were prepared with lipophilicity through a facile one-pot hydrothermal carbonization of chloranil and triethylenetetramine at 160 °C for 3 h. The as-obtained CDs are proved to have good photostability, low cost, and excellent biocompatibility. Importantly, the as-prepared CDs with high quantum yield of 30.8% show excitation-dependent emission with great stability, and thus, they can be well used for the long-term target imaging of lysosomes in living cells without further modification. Meanwhile, the CDs can quickly enter into the lysosomes within 30 min, and the green fluorescence (FL) of CDs reaches the plateau when incubated for 60 min. By comparing the fluorescent intensity, the information about distribution and amount of lysosomes in different cells can be obtained. The proposed CD-based strategy demonstrates great promise for label-free target imaging of lysosomes in living cells. Graphical abstract The near-neutral carbon dots (CDs) with lipophilicity are used as label-free fluorescent nanoprobes for the long-term imaging of lysosomes in living cells.

Water disinfection, primarily by chlorination, is one of the greatest achievements of public health. However, more than half a century after its introduction, studies in the 1970s reported that (a) chlorine interacted with organic matter in the water to form disinfection by-products (DBPs); (b) two DBPs, chloroform and bromoform, both trihalomethanes (THMs), were rodent carcinogens; (c) three brominated THMs were mutagenic; in six studies chlorinated drinking waters in the United States and Canada were mutagenic; and (d) in one epidemiological study there was an association between bladder cancer mortality and THM exposure. This led the U.S. Environmental Protection Agency to issue its first DBP regulation in 1979. Forty years later, >600 DBPs have been characterized, 20/22 have been shown to be rodent carcinogens, >100 have been shown to be genotoxic, and 1000s of water samples have been found to be mutagenic. Data support a hypothesis that long-term dermal/inhalation exposure to certain levels of the three brominated THMs, as well as oral exposure to the haloacetic acids, combined with a specific genotype may increase the risk for bladder cancer for a small but significant population group. Improved water-treatment methods and stricter regulations have likely reduced such risks over the years, and further reductions in potential risk are anticipated with the application of advanced water-treatment methods and wider application of drinking water regulations. This 40-year research effort is a remarkable example of sustained cooperation between academic and government scientists, along with public/private water companies, to find answers to a pressing public health question., (Published 2020. This article is a U.S. Government work and is in the public domain in the USA.)