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Chemical research in toxicology
American Chemical Society
Chemical research in toxicology

American Chemical Society

0893-228X

Chemical research in toxicology/Journal Chemical research in toxicologySCIISTPICCCR
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    50 Years of Research on Tobacco-Specific Nitrosamines: A Virtual Collection of Emerging Knowledge of Chemical Toxicology of Tobacco and Nicotine Delivery Systems and Call for Contributions to a Landmark Special Issue

    Hecht, Stephen S.Gupta, Prakash ChandraSturla, Shana J.Wang, Yinsheng...
    2页
      原文链接:
    • NSTL
    • Amer Chemical Soc

    Hair Dye Ingredients and Potential Health Risks from Exposure to Hair Dyeing

    He, LinMichailidou, FreiderikiGahlon, Hailey L.Zeng, Weibin...
    15页
    查看更多>>摘要：Given the worldwide popularity of hair dyeing, there is an urgent need to understand the toxicities and risks associated with exposure to chemicals found in hair dye formulations. Hair dyes are categorized as oxidative and nonoxidative in terms of their chemical composition and ingredients. For several decades, the expert panel's Cosmetic Ingredient Review (CIR) has assessed the safety of many of the chemicals used in hair dyes; however, a comprehensive review of hair dye ingredients and the risk of exposure to hair dyeing has not been documented. Herein, we review the safety of the various chemicals in oxidative and nonoxidative hair dyes, toxicities associated with hair dyeing, and the carcinogenic risks related to hair dyeing. While many compounds are considered safe for users at the concentrations in hair dyes, there are conflicting data about a large number of hair dye formulations. The CIR expert panel has ratified a number of coloring ingredients for hair dyes and banned a series of chemicals as carcinogenic to animals and unsafe for this application. The use of these chemicals as raw materials for producing hair dyes may result in the synthesis of other contaminants with potential toxicities and increased risk of carcinogenesis. It is an open question whether personal or occupational hair dyeing increases the risk of cancer; however, in specific subpopulations, a positive association between hair dye use and cancer occurrence has been reported. To address this question, a better understanding of the chemical and mechanistic basis of the reported toxicities of hair dye mixtures and individual hair dye ingredients is needed. It is anticipated that in-depth chemical and systems toxicology studies harnessing modern and emerging techniques can shed light on this public health concern in the future.
      原文链接:
    • NSTL
    • Amer Chemical Soc

    Phytochemicals in the Management of Arsenic Toxicity

    Khan, Sabiya SamimSharma, AnkitaFlora, Swaran J. S.
    19页
    查看更多>>摘要：Arsenic toxicity is a major concern due to its deleterious consequences for human health. Rapid industrialization also has weakened the quality of the environment by introducing pollutants that may disrupt balanced ecosystems, adversely and irreversibly impacting humans, plants, and animals. Arsenic, an important toxicant among all environmental hazards, can lead to several detrimental effects on cells and organs, impacting the overall quality of life. Nevertheless, arsenic also has a rich history as a chemotherapeutic agent used in ancient days for the treatment of diseases such as malaria, cancer, plague, and syphilis when other chemotherapeutic agents were yet to be discovered. Arsenicosis-mediated disorders remain a serious problem due to the lack of effective therapeutic options. Initially, chelation therapy was used to metabolically eliminate arsenic by forming a complex, but adverse effects limited their pharmacological use. More recently, plant-based products have been found to provide significant relief from the toxic effects of arsenic poisoning. They act by different mechanisms affecting various cellular processes. Phytoconstituents such as curcumin, quercetin, diallyl trisulfide, thymoquinone, and others act via various molecular pathways, primarily by attenuating oxidative damage, membrane damage, DNA damage, and proteinopathies. Nonetheless, most of the phytochemicals reviewed here protect against the adverse effects of metal or metalloid exposure, supporting their consideration as alternatives to chelation therapy. These agents, if used prophylactically and in conjunction with other chemotherapeutic agents, may provide an effective approach for management of arsenic toxicity. In a few instances, such strategies like coadministration of phytochemicals with a known chelating agent have led to more pronounced elimination of arsenic from the body with lesser off-site adverse effects. This is possible because combination treatment ensures the use of a reduced dose of chelating agent with a phytochemical without compromising treatment. Thus, these therapies are more practical than conventional therapeutic agents in ameliorating arsenic-mediated toxicity. This review summarizes the potential of phytochemicals in alleviating arsenic toxicity on the basis of available experimental and clinical evidence.
      原文链接:
    • NSTL
    • Amer Chemical Soc

    Human TREX1 Repairs 3 '-End DNA Lesions in Vitro

    Yang, KunWei, XiaoyingLe, JenniferRodriguez, Nestor...
    5页
    查看更多>>摘要：Human three-prime repair exonuclease 1 (TREX1) is the major 3' to 5' exonuclease that functions to deplete the cytosolic DNA to prevent the autoimmune response. TREX1 is upregulated and translocates from cytoplasm to the nucleus in response to genotoxic stress, but the function of nuclear TREX1 is not well understood. Herein, we wish to report our in vitro finding that TREX1 efficiently excises 3'-phospho-alpha,beta-unsaturated aldehyde and 3'-deoxyribose phosphate that are commonly produced as base excision repair intermediates and also from the nonenzymatic strand incision at abasic sites.
      原文链接:
    • NSTL
    • Amer Chemical Soc

    Hydrogen Cyanide and Aromatic Amine Yields in the Mainstream Smoke of 60 Little Cigars

    Ai, JiuHassink, MatthewTaylor, Kenneth M.Deycard, Victoria Nicole...
    14页
    查看更多>>摘要：Mainstream smoke yields of hydrogen cyanide (HCN) and three aromatic amines, 1-aminonaphthalene, 2-aminonaphthalene, and 4-aminobiphenyl, from 60 little cigar brands currently on the US market were measured for both International Organization for Standardization (ISO) and Canadian Intense (CI) smoking regimens. The smoke yields are compared with those from 50 cigarette products measured by Counts et al. of Philip Morris USA (PMUSA) in 2005 [Counts et al. Regul. Toxicol. Pharmacol. 2005 41, 185-227] and 50 cigarette products measured by the Centers for Disease Control and Prevention (CDC) in cooperation with the Food and Drug Administration (FDA) in 2012 [Tynan et al. Consumption of Cigarettes and Combustible Tobacco: United States, 2000-2011. In Morbidity and Mortality Weekly Report; Centers for Disease Control and Prevention, 2012; 565-580]. For the little cigars, the average HCN yield with the ISO smoking regimen is 335 mu g/cigar (range: 77-809 mu g/cigar), which is 332% higher than the average of 50 PMUSA 2005 cigarettes and 243% higher than the average of 50 CDC/FDA 2012 cigarettes. For the CI smoking regimen, the average HCN yield is 619 mu g/cigar (range: 464-1045 mu g/cigar), which is 70.5% higher than the average of 50 PMUSA 2005 cigarettes and 69% higher than the average of the 50 CDC/FDA 2012 cigarettes. For aromatic amines, the average ISO smoking regimen smoke yields are 36.6 ng/cigar (range: 15.9-70.6 ng/cigar) for 1-aminonaphthalene, 24.6 ng/cigar (range: 12.3-36.7 ng/cigar) for 2-aminonaphthalene, and 5.6 ng/cigar (range: 2.3-17.2 ng/cigar) for 4-aminobiphenyl. The average ISO yields of aromatic amines from little cigars are 141% to 210% higher compared to the average yields of 50 PMUSA cigarettes. The average CI smoke regimen yields are 73.0 ng/cigar (range: 32.1-112.2 ng/cigar) for 1-aminonaphthalene, 45.2 ng/cigar (range: 24.6-74.8 ng/cigar) for 2-aminonaphthalene, and 12.7 ng/cigar (range: 5.5-37.5 ng/cigar) for 4-aminobiphenyl. The average CI aromatic amine yields are 143% to 220% higher compared to the average yields of 50 PMUSA cigarettes, almost identical to the relative yields under the ISO smoking regimen. Both HCN and aromatic amine yields are 1.5x to 3x higher for the tested little cigars than for the conventional cigarettes; however, there are notable differences in the relationships of these yields to certain product characteristics, such as weight, ventilation, and tobacco type. The higher smoke yields of these compounds from little cigars indicates that cigar smokers may be at risk of a higher exposure to HCN and aromatic amines on a per stick basis and thus increased health concerns.
      原文链接:
    • NSTL
    • Amer Chemical Soc

    Examining Metal Contents in Primary and Secondhand Aerosols Released by Electronic Cigarettes

    Kapiamba, Kashala FabriceHao, WeixingAdom, StephenLiu, Wenyan...
    9页
    查看更多>>摘要：The usage of electronic cigarettes (ECs) has surged since their invention two decades ago. However, to date, the health effects of EC aerosol exposure are still not well understood because of insufficient data on the chemical composition of EC aerosols and the corresponding evidence of health risks upon exposure. Herein, we quantified the metals in primary and secondhand aerosols generated by three brands of ECs. By combining aerosol filter sampling and inductively coupled plasma mass spectrometry (ICP-MS), we assessed the mass of metals as a function of EC flavoring, nicotine concentration, device power, puff duration, and aging of the devices. The masses of Cr, Cu, Mn, Ni, Cu, and Zn were consistently high across all brands in the primary and secondhand aerosols, some of which were above the regulated maximum daily intake amount, especially for Cr and Ni with mass (nanograms per 10 puffs) emitted at 117 +/- 54 and 50 +/- 24 (JUUL), 125 +/- 77 and 219 +/- 203 (VOOPOO), and 33 +/- 10 and 27 +/- 2 (Vapor4Life). Our analysis indicates that the metals are predominantly released from the EC liquid, potentially through mechanisms such as bubble bursting or the vaporization of metal-organic compounds. High metal contents were also observed in simulated secondhand aerosols, generally 80-90% of those in primary aerosols. Our findings provide a more detailed understanding of the metal emission characteristics of EC for assessing its health effects and policymaking.
      原文链接:
    • NSTL
    • Amer Chemical Soc

    Dissolution Rate of Nanomaterials Determined by Ions and Particle Size under Lysosomal Conditions: Contributions to Standardization of Simulant Fluids and Analytical Methods

    Zanoni, IlariaKeller, Johannes G.Sauer, Ursula G.Mueller, Philipp...
    18页
    查看更多>>摘要：Dissolution of inhaled engineered nanomaterials (ENM) under physiological conditions is essential to predict the clearance of the ENM from the lungs and to assess their biodurability and the potential effects of released ions. Alveolar macrophage (AM) lysosomes contain a pH 4.5 saline brine with enzymes and other components. Different types of artificial phagolysosomal simulant fluids (PSFs) have been developed for dissolution testing, but the consequence of using different media is not known. In this study, we tested to which extent six fundamentally different PSFs affected the ENM dissolution kinetics and particle size as determined by a validated transmission simulant media were consistent with each other and with in vivo clearance. These media predict the quick dissolution of ZnO, the partial dissolution of SiO2, and the very slow dissolution of TiO2. The valid media use either a mix of organic acids (with the total concentration below 0.5 g/L, thereof citric acid below 0.15 g/L) or another organic acid (KH phthalate). For several ENM, including ZnO, BaSO4, and CeO2, all these differences induce only minor modulation of the dissolution rates. Only for TiO2 and SiO2, the interaction with specific organic acids is highly sensitive, probably due to sequestration of the ions, and can lead to wrong predictions when compared to the in vivo behavior. The media that fail on TiO2 and SiO2 dissolution use citric acid at concentrations above 5 g/L (up to 28 g/L). In the present selection of ENM, fluids, and methods, the different lysosomal simulant fluids did not induce changes of particle morphology, except for small changes in SiO2 and BaSO4 particles most likely due to ion dissolution, reprecipitation, and coalescence between neighboring particles. Based on the current evidence, the particle size by TEM analysis is not a sufficiently sensitive analytical method to deduce the rate of ENM dissolution in physiological media. In summary, we recommend the standardization of ENM dissolution testing by one of the three valid lysosomal simulant fluids with determination of the dissolution rate and halftime by the quantification of ions. This recommendation was established for a continuous flow system but may be relevant as well for static (batch) solubility testing.
      原文链接:
    • NSTL
    • Amer Chemical Soc

    LA-ICP-MS and Immunohistochemical Staining with Lanthanide-Labeled Antibodies to Study the Uptake of CeO2 Nanoparticles by Macrophages in Tissue Sections

    Seiffert, Svenja B.Vennemann, AntjeNordhorn, Ilona D.Kroeger, Sabrina...
    11页
    查看更多>>摘要：Due to the increasing use and production of CeO2 nanoparticles (NPs), the likelihood of exposure especially via the air rapidly grows. However, the uptake of CeO2 NPs via the lung and the resulting distribution into various cell types of remote organs are not well understood because classical analytical methods provide limited spatial information. In this study, laser ablation- inductively coupled plasma-mass spectrometry (LA-ICP-MS) was combined with immunohistochemical (IHC) staining with lanthanide-labeled antibodies to investigate the distribution of intratracheally instilled CeO2 NPs from the rat lung to lymph nodes, spleen, and liver after 3 h, 3 days, and 21 days. We selected regions of interest after fast imaging using LA-ICP-MS in low-resolution mode and conducted high-resolution LA-ICP-MS in combination with IHC for cellular localization. The lanthanide labeling, which was largely congruent with conventional fluorescent labeling, allowed us to calculate the association rates of Ce to specific cell types. Major portions of Ce were found to be associated with phagocytic cells in the lung, lymph nodes, spleen, and liver. In the lung, almost 94% of the Ce was co-localized with CD68-positive alveolar macrophages after 21 days. Ce was also detected in the lymph nodes outside macrophages 3 h post instillation but shifted to macrophage-associated locations. In the liver, Ce accumulations associated with Kupffer cells (CD163-positive) were found. Ce-containing populations of metallophilic and marginal zone macrophages (both CD169-positive) as well as red pulp macrophages (CD68-positive) were identified as major targets in the spleen. Overall, high-resolution LA-ICP-MS analysis in combination with IHC staining with lanthanide-labeled antibodies is a suitable tool to quantify and localize Ce associated with specific cell types and to estimate their particle burden under in vivo conditions.
      原文链接:
    • NSTL
    • Amer Chemical Soc

    Mixtures-Inclusive In Silico Models of Ocular Toxicity Based on United States and International Hazard Categories

    Choksi, Neepa Y.Allen, David G.Casey, Warren M.Shah, Ruchir...
    9页
    查看更多>>摘要：Computational modeling grounded in reliable experimental data can help design effective non-animal approaches to predict the eye irritation and corrosion potential of chemicals. The National Toxicology Program (NTP) Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM) has compiled and curated a database of in vivo eye irritation studies from the scientific literature and from stakeholder-provided data. The database contains 810 annotated records of 593 unique substances, including mixtures, categorized according to UN GHS and US EPA hazard classifications. This study reports a set of in silico models to predict EPA and GHS hazard classifications for chemicals and mixtures, accounting for purity by setting thresholds of 100% and 10% concentration. We used two approaches to predict classification of mixtures: conventional and mixture-based. Conventional models evaluated substances based on the chemical structure of its major component. These models achieved balanced accuracy in the range of 68-80% and 87-96% for the 100% and 10% test concentration thresholds, respectively. Mixture-based models, which accounted for all known components in the substance by weighted feature averaging, showed similar or slightly higher accuracy of 72-79% and 89-94% for the respective thresholds. We also noted a strong trend between the pH feature metric calculated for each substance and its activity. Across all the models, the calculated pH of inactive substances was within one log10 unit of neutral pH, on average, while for active substances, pH varied from neutral by at least 2 log10 units. This pH dependency is especially important for complex mixtures. Additional evaluation on an external test set of 673 substances obtained from ECHA dossiers achieved balanced accuracies of 64-71%, which suggests that these models can be useful in screening compounds for ocular irritation potential. Negative predictive value was particularly high and indicates the potential application of these models in a bottom-up approach to identify nonirritant substances.
      原文链接:
    • NSTL
    • Amer Chemical Soc

    Neutrophil Myeloperoxidase-Mediated N-Demethylation of Quetiapine Leads to N-Desalkylquetiapine, a Pharmacologically Active Cytochrome P450 Metabolite

    Rashid, Md HarunurBabu, DineshTran, NewtonReiz, Bela...
    10页
    查看更多>>摘要：The atypical antipsychotic drugs, quetiapine and clozapine, are associated with idiosyncratic drug reactions (such as agranulocytosis or neutropenia) that are thought to involve reactive metabolites. Neutrophil myeloperoxidase (MPO) metabolism of quetiapine is not well-studied, but is metabolized by cytochrome P450. Based on structural similarity to clozapine, we hypothesized that quetiapine can be metabolized by MPO and that there is overlap between cytochrome P450 and MPO metabolism of quetiapine. The interaction of quetiapine and clozapine with MPO and MPO chlorination activity was studied using UV-vis spectrophotometry. The metabolites were characterized using liquid chromatography-mass spectrometry (LC-MS), and electron paramagnetic resonance (EPR) spectroscopy was used for detecting drug-catalyzed glutathione oxidation. In the presence of quetiapine, MPO compound II accumulated for about 7.5 min, whereas in the presence of clozapine, MPO compound II was not observed as it was rapidly reduced back to the resting state. Increasing quetiapine concentrations resulted in a decrease in MPO chlorination activity, while the opposite result was found in the case of clozapine. UV-vis spectral studies showed no change when quetiapine was oxidized in the absence and presence of chloride anion (Cl- , to catalyze chlorination reactions). Significant changes, however, were observed in the same assay with clozapine, where Cl- appeared to hinder the rate of clozapine metabolism. The MPO-catalyzed hydroxylated and dealkylated metabolites of quetiapine and hydroxylated metabolites of clozapine were observed from the LC-MS analyses, particularly when Cl- was included in the reaction. In addition, hydroxylated, dealkylated, and a proposed sulfoxide metabolite of quetiapine were also observed in the reaction catalyzed by human microsomes/NADPH. Lastly, compared to quetiapine, clozapine metabolism by MPO/H2O2 and glutathione produced more glutathionyl radicals using EPR spin trapping. In conclusion, MPO/H2O2/Cl- was shown to metabolize quetiapine to S-oxidation and P450-like dealkylation products, and quetiapine metabolites were generally less reactive than clozapine.
      原文链接:
    • NSTL
    • Amer Chemical Soc