Assessing Toxicity and in Vitro Bioactivity of Smoked Cigarette Leachate Using Cell-Based Assays and Chemical Analysis
- Elvis Genbo XuElvis Genbo XuDepartment of Environmental Sciences, University of California, Riverside, Riverside, California 92521, United StatesMore by Elvis Genbo Xu
- William H. RichardotWilliam H. RichardotSchool of Public Health, San Diego State University, San Diego, California 92182, United StatesSan Diego State University Research Foundation, San Diego, California 92182, United StatesMore by William H. Richardot
- Shuying LiShuying LiDepartment of Environmental Sciences, University of California, Riverside, Riverside, California 92521, United StatesMore by Shuying Li
- Lucas BuruaemLucas BuruaemDepartment of Environmental Sciences, University of California, Riverside, Riverside, California 92521, United StatesMore by Lucas Buruaem
- Hung-Hsu WeiHung-Hsu WeiSchool of Public Health, San Diego State University, San Diego, California 92182, United StatesMore by Hung-Hsu Wei
- Nathan G. DodderNathan G. DodderSchool of Public Health, San Diego State University, San Diego, California 92182, United StatesSan Diego State University Research Foundation, San Diego, California 92182, United StatesMore by Nathan G. Dodder
- Suzaynn F. SchickSuzaynn F. SchickDepartment of Medicine, Division of Occupational and Environmental Health, University of California, San Francisco San Francisco, California 94143, United StatesMore by Suzaynn F. Schick
- Thomas NovotnyThomas NovotnySchool of Public Health, San Diego State University, San Diego, California 92182, United StatesSan Diego State University Research Foundation, San Diego, California 92182, United StatesMore by Thomas Novotny
- Daniel SchlenkDaniel SchlenkDepartment of Environmental Sciences, University of California, Riverside, Riverside, California 92521, United StatesMore by Daniel Schlenk
- Richard M. GersbergRichard M. GersbergSchool of Public Health, San Diego State University, San Diego, California 92182, United StatesMore by Richard M. Gersberg
- Eunha Hoh*Eunha Hoh*E-mail: [email protected]. Phone: (619) 594-4671.School of Public Health, San Diego State University, San Diego, California 92182, United StatesMore by Eunha Hoh
Abstract

Smoked cigarettes are the most prevalent form of litter worldwide, often finding their way into oceans and inland waterways. Cigarette smoke contains more than 4000 individual chemicals, some of them carcinogenic or otherwise toxic. We examined the cytotoxicity, genotoxicity, aryl hydrocarbon receptor (AhR), estrogen receptor (ER), and p53 response pathways of smoked cigarette leachate in vitro. Both seawater and freshwater leachates of smoked cigarettes were tested. Cytotoxicity and genotoxicity were negligible at 100 smoked cigarettes/L, while statistically significant AhR, ER, and p53 responses were observed in the extracts of both leachates, suggesting a potential risk to human health through exposure to cigarette litter in the environment. To identify responsible chemicals for the AhR response, an effect directed analysis approach was coupled with nontargeted chemical analysis based on comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry (GC × GC/TOF-MS). Eleven compounds potentially responsible for the AhR response were identified. Among them, 2-methylindole was partially responsible for the AhR response.
Introduction
Figure 1

Figure 1. (a) Overall experimental design. SCL was tested in vitro for toxicity, estrogen receptor, AhR, and p53 response. SCL was then separated into fractions by polarity and retested in assays that exhibited a positive response during initial toxicological testing. Following testing of SCL fractions, the nontargeted chemical analysis was performed to identify compounds potentially responsible for biological response. (b) Steps of chemical data analysis. Nontargeted chemical analysis of SCL was conducted to isolate all compounds uniquely found in SCL fractions that exhibited biological response. All compounds were first screened for their absence in control samples and compiled into a preliminary list of potential compounds. Compounds from the preliminary list were then organized by the SCL fractions in which they were found. Compounds found only in fractions exhibiting biological response were then considered for confirmation with an authentic reference standard.
Materials and Methods
Chemicals
Leachate Preparation
SPE Extraction and Fractionation for Bioassays
MTT Bioassay
ER, AhR, and p53 Activity Assays
Genotoxicity Assay
Chemical Analysis of SPE Fractions
Results
Cytotoxicity and Cellular Activities of SCL
Figure 2

Figure 2. Cytotoxicity of 10 cig/L, 100 cig/L, and SPE-extracted 100 cig/L SCL samples in (a, b) AhR cells, (c) ER cells, and (d) p53 cells. Mean ± SD, n = 3. FW, freshwater; SW, seawater; and SPE, solid-phase extracted sample. Number n in the sample code indicates dilution of 2n times (dilution factors range from 2 to 64).
Figure 3

Figure 3. Bioactivities of 10 cig/L, 100 cig/L, and SPE-extracted 100 cig/L SCL samples. (a) RLU of E2 and samples, (b) blue/green ratio of PCB126 and samples, and (c) blue/green ratio of mitomycin and samples. The horizontal dotted line in (a–c) indicates the benchmark of activity. SW, seawater; FW, freshwater; 10cig, 10 cig/L sample; 100cig, 100 cig/L sample; and SPE, solid-phase extracted sample. Triangles represent seawater tests and circles represent freshwater tests. (d) The mean aryl hydrocarbon toxicity equivalents (TEQ) of fractionated (eluted by 10%, 25%, 50%, 75%, and 100% MeOH/H2O in order or 100% MeOH only) seawater and freshwater SCL samples (mean ± SD, n = 3).
| EEQ (pg/L) | TEQ (pg/L) | MCQ (μg/L) | |
|---|---|---|---|
| SWctrl | <29.3 | <0.17 | 1.4 ± 0.2 |
| SW10cig | <29.3 | <0.17 | 2.1 ± 0.2 |
| SW100cig | <29.3 | 13.2 ± 0.6* | 26.1 ± 2.3* |
| SW100cigSPE | 85.0 ± 11.1* | 2,660 ± 109* | 41.9 ± 5.9* |
| FWctrl | <29.3 | <0.17 | <1.7 |
| FW10cig | <29.3 | 10.1 ± 8.2 | <1.7 |
| FW100cig | <29.3 | 22.8 ± 0.5* | 21.1 ± 1.0* |
| FW100cigSPE | <29.3 | 45.6 ± 0.3* | 30.3 ± 2.9* |
Asterisk indicates a significant difference with control (p < 0.05); mean ± SD, n = 3.
Cytotoxicity, Genotoxicity, and AhR Activity of SCL Extract Fractions
Figure 4

Figure 4. Genotoxicity of fractionated SCL samples. IR was calculated as a quantitative measure of the genotoxicity of fractionated samples. For each sample dilution, β-galactosidase activity and growth factor were combined to form the IR. SW samples showed higher IRs than FW samples, but the growth factors were below 0.5 for all samples, suggesting their negligible genotoxicity. FW, freshwater; SW, seawater; SPE, solid-phase extracted sample. Mean ± SD, n = 3.
Chemical Analysis
Figure 5

Figure 5. Peak true mass spectra of the five identifiable compounds and their matching mass spectra in the NIST database.
| analyte | CAS registry number | 1D, 2D retention time | peak area freshwater | peak area saltwater | quant ion | molecular weight | similarity score | level of identification |
|---|---|---|---|---|---|---|---|---|
| 2-methylindole | 95-20-5 | 2298.96, 1.934 | 27780 | 10324 | 130 | 131.17 | 878 | confirmed by authentic standard |
| 5H-1-pyridine | 270-91-7 | 2057.6, 1.960 | 47762 | 9847.8 | 117 | 117.15 | 910 | strong mass spectra match |
| benzamide, N-propyl- | 10546-70-0 | 3967.51, 1.261 | 237251 | 248528 | 105 | 163.22 | 972 | strong mass spectra match; not matched by authentic standard |
| cinnamic acid, β-[N-benzoylamino]-3,4-dihydroxy- | 143815-48-9 | 2739.71, 1.604 | 3655.5 | 2984.3 | 105 | 299.28 | 845 | strong mass spectra match |
| diethyl phthalate | 84-66-2 | 2781.68, 1.802 | 16524 | 3226.2 | 149 | 222.24 | 946 | confirmed by authentic standard |
Quantification of 2-MI and AhR Activity Test
Figure 6

Figure 6. Cytotoxicity (left) and AhR activity (right) of 2-MI expressed as relative cell availability and blue/green ratio, respectively. Mean ± SD, n = 3.
Discussion
Limitations and Implications
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.chemrestox.9b00201.
Mass spectra of unknown compounds found in AhR-responsive samples; instrument conditions of GC × GC/TOF-MS for the chemical analyses; and chemical analysis information on six unknown compounds found in AhR-responsive samples (PDF)
Department of Chemical Engineering, McGill University, Montréal, Quebec H3A 0C5, Canada
The authors declare no competing financial interest.
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Acknowledgments
This project was funded by California Tobacco Related Disease Research Program (TRDRP: 23RT-0014H). We thank Adam Whitlatch for producing smoked cigarettes (cigarette butts), Kayo Watanabe for technical assistance on sample extraction and instrumentation, and Nautilus Environmental San Diego Laboratory for assistance on the generation of the smoked cigarette leachate.
References
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- 17Begum, A. N., Aguilar, J. S., and Hong, Y. (2017) Aqueous cigarette tar extracts disrupt corticogenesis from human embryonic stem cells in vitro. Environ. Res. 158, 194– 202, DOI: 10.1016/j.envres.2017.06.012[Crossref], [PubMed], [CAS], Google Scholar17https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtVKgu7zI&md5=1822527c875a4a8da982e4baea1cdeefAqueous cigarette tar extracts disrupt corticogenesis from human embryonic stem cells in vitroBegum, Aynun N.; Aguilar, Jose S.; Hong, YilingEnvironmental Research (2017), 158 (), 194-202CODEN: ENVRAL; ISSN:0013-9351. (Elsevier)Cigarette butts are the most common form of litter in the world, and approx. 4.5 trillion smoked cigarettes are discarded every year worldwide. Cigarette butts contain over 4000 chems., many of which are known to have neurotoxic effects. Stem cell neuronal differentiation provides an excellent cellular model with which to examine the impact of aq. cigarette tar exts. (ACTEs) on neurodevelopment. We have developed a neurosphere-based stem cell neuronal differentiation protocol that can recapitulate corticogenesis and produce cell types that are similar to upper and lower layer cortical projection neurons found in the germinal zone of the developing human cortex. In this study, ACTEs were generated from smoked cigarette butts and then applied at different concns. to neuronal progenitors and cortical neurons derived from human embryonic stem cells. ACTEs reduced the expression of the cortical neuronal progenitor markers pax6, tbr2, and neuroD and decreased the no. of cortical layer neurons (tbr1, satb2, foxp2, and brn2) after exposure to as low as 1.87% of the ext. from one smoked cigarette butt. Furthermore, our results showed that ACTEs increased reactive oxygen species (ROS) prodn. in cortical neurons, which caused a substantial loss of the synaptic proteins PSD95, synaptophysin, vesicular glutamate transporter1 (vGlut1), and the extracellular matrix mol. reelin; all of those mols. are important for the maintenance of cortical neuron identity and activity. ACTEs from smoked cigarettes have significant effects on cortical neuron development and neurodegeneration. The stem cell neuronal differentiation model holds great promise as a potentially powerful tool for the assessment of ACTEs on neurotoxicity.
- 18Denison, M. S. and Nagy, S. R. (2003) Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals. Annu. Rev. Pharmacol. Toxicol. 43 (1), 309– 334, DOI: 10.1146/annurev.pharmtox.43.100901.135828[Crossref], [PubMed], [CAS], Google Scholar18https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXitFWqtr8%253D&md5=612df556e0644f9dd165bedc13fd7bf0Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicalsDenison, Michael S.; Nagy, Scott R.Annual Review of Pharmacology and Toxicology (2003), 43 (), 309-334CODEN: ARPTDI; ISSN:0362-1642. (Annual Reviews Inc.)A review. The induction of expression of genes for xenobiotic metabolizing enzymes in response to chem. insult is an adaptive response found in most organisms. In vertebrates, the AhR is one of several chem./ligand-dependent intracellular receptors that can stimulate gene transcription in response to xenobiotics. The ability of the AhR to bind and be activated by a range of structurally divergent chems. suggests that the AhR contains a rather promiscuous ligand binding site. In addn. to synthetic and environmental chems., numerous naturally occurring dietary and endogenous AhR ligands have also been identified. In this review, we describe evidence for the structural promiscuity of AhR ligand binding and discuss the current state of knowledge with regards to the activation of the AhR signaling pathway by naturally occurring exogenous and endogenous ligands.
- 19Dertinger, S. D., Silverstone, A. E., and Gasiewicz, T. A. (1998) Influence of aromatic hydrocarbon receptor-mediated events on the genotoxicity of cigarette smoke condensate. Carcinogenesis 19 (11), 2037– 2042, DOI: 10.1093/carcin/19.11.2037[Crossref], [PubMed], [CAS], Google Scholar19https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXnvVCmsrs%253D&md5=d0965b274f91b88494b72085388c39cfInfluence of aromatic hydrocarbon receptor-mediated events on the genotoxicity of cigarette smoke condensateDertinger, Stephen D.; Silverstone, Allen E.; Gasiewicz, Thomas A.Carcinogenesis (1998), 19 (11), 2037-2042CODEN: CRNGDP; ISSN:0143-3334. (Oxford University Press)The role of arom. hydrocarbon receptor (AhR)-mediated events on the genotoxicity of mainstream cigarette smoke condensate was investigated. In vitro studies with mouse hepatoma cells stably transfected with a DRE-dependent luciferase reporter indicate that cigarette smoke condensate is able to transform AhR to an active form which is capable of initiating gene transcription. Micronucleus formation in two hepatoma cell lines was used as an index of genotoxicity. Cigarette smoke condensate was obsd. to induce a higher frequency of micronuclei in Hepa1c1c7 cells relative to TAOc1BPrc1 cells, which express ∼10-fold less AhR. Furthermore, the frequency of micronuclei was potentiated when Hepa1c1c7 cells were pretreated with 2,3,7,8-tetrachlorodibenzo-p-dioxin, a high affinity ligand of AhR. These in vitro studies were followed by an in vivo expt. with Ahr+/+ and Ahr-/- mice. Animals were dosed for three consecutive days with cigarette smoke condensate (0.5-10 μg/kg/day, i.p. injection). The frequency of micronuclei in reticulocytes and total erythrocytes was detd. in peripheral blood samples collected 24 h after the last administration. While condensate was found to increase the incidence of micronucleated reticulocytes in Ahr+/+ mice, no increase was obsd. in the null allele animals. Furthermore, the frequency of micronucleated erythrocytes, a measure of basal chromosome-damaging activity, was slightly but significantly higher in Ahr+/+ relative to Ahr-/- mice. Together, these data suggest that cigarette smoke contains chems. which transform the AhR to an active transcription factor and AhR-regulated enzyme induction plays an important role in mediating the genotoxicity of this complex environmental pollutant.
- 20Ono, Y., Torii, K., Fritsche, E., Shintani, Y., Nishida, E., Nakamura, M., Shirakata, Y., Haarmann-Stemmann, T., Abel, J., Krutmann, J., and Morita, A. (2013) Role of the aryl hydrocarbon receptor in tobacco smoke extract-induced matrix metalloproteinase-1 expression. Exp. Dermatol. 22 (5), 349– 353, DOI: 10.1111/exd.12148[Crossref], [PubMed], [CAS], Google Scholar20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtVWmsrbL&md5=c3506da4a84759de6f76aada6ec21c1cRole of the aryl hydrocarbon receptor in tobacco smoke extract-induced matrix metalloproteinase-1 expressionOno, Yuko; Torii, Kan; Fritsche, Ellen; Shintani, Yoichi; Nishida, Emi; Nakamura, Motoki; Shirakata, Yuji; Haarmann-Stemmann, Thomas; Abel, Josef; Krutmann, Jean; Morita, AkimichiExperimental Dermatology (2013), 22 (5), 349-353CODEN: EXDEEY; ISSN:1600-0625. (Wiley-Blackwell)Findings from large epidemiol. studies indicate that there is a link between smoking and extrinsic skin ageing. We previously reported that matrix metaUoproteinases (MMPs) mediate connective tissue damage in skin exposed to tobacco smoke exts. Tobacco smoke contains more than 3800 constituents, including numerous water-insol. polycyclic arom. hydrocarbons (PAHs) that trigger aryl hydrocarbon receptor (AhR) signalling pathways. To analyze the mol. mechanisms involved in tobacco smoke-induced skin ageing, we exposed primary human fibroblasts and keratinocytes to tobacco smoke exts. Hexane- and water-sol. tobacco smoke exts. significantly induced MMP-1 mRNA in both human cultured fibroblasts and keratinocytes in a dose-dependent manner. To clarify the involvement of the AhR pathway, we used a stable AhR-knockdown HaCaT cell line. AhR knockdown abolished the increased transcription of the AhR-dependent genes CYP1A1/CYP1B1 and MMP-1 induced by either of the tobacco smoke exts. Furthermore, the tobacco smoke exts. induced 7-ethoxyresorufin-O-deethylase activity, which was almost completely abolished by AhR knockdown. Likewise, treating fibroblasts with AhR pathway inhibitors, i.e., the flavonoids 3-methoxy-4-nitroflavone and α-naphthoflavone, blocked the expression of CYP1B1 and MMP-1. These findings suggest that the tobacco smoke exts. induce MMP-1 expression in human fibroblasts and keratinocytes via activation of the AhR pathway. Thus, the AhR pathway may be pathogenetically involved in extrinsic skin ageing.
- 21Kitamura, M. and Kasai, A. (2007) Cigarette smoke as a trigger for the dioxin receptor-mediated signaling pathway. Cancer Lett. 252 (2), 184– 194, DOI: 10.1016/j.canlet.2006.11.015[Crossref], [PubMed], [CAS], Google Scholar21https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXlvVyitLg%253D&md5=30b74c90b55f70897d03cce6fb7e7008Cigarette smoke as a trigger for the dioxin receptor-mediated signaling pathwayKitamura, Masanori; Kasai, AyumiCancer Letters (Amsterdam, Netherlands) (2007), 252 (2), 184-194CODEN: CALEDQ; ISSN:0304-3835. (Elsevier B.V.)A review and discussion. Dioxins and dioxin-like chems. cause a wide range of pathologies including carcinogenesis, immune dysfunction, and developmental/reproductive abnormalities. Most of these toxic effects are mediated by aryl hydrocarbon receptor (AhR; also called the dioxin receptor), a ligand-activated transcription factor. Constitutive activation of AhR via genetic manipulation causes development of cancers, inflammation and immune abnormality in mice even without exposure to xenobiotic ligands. Recent investigation disclosed that cigarette smoke contains high levels of agonists for AhR and strongly activates the dioxin signaling pathway. In this review, the authors describe and discuss possible roles of AhR activation in cigarette smoke-related pathologies, esp., focusing on carcinogenesis, inflammation, atherosclerosis, immune dysfunction and teratogenesis.
- 22Meek, M. D. and Finch, G. L. (1999) Diluted mainstream cigarette smoke condensates activate estrogen receptor and aryl hydrocarbon receptor-mediated gene transcription. Environ. Res. 80 (1), 9– 17, DOI: 10.1006/enrs.1998.3872[Crossref], [PubMed], [CAS], Google Scholar22https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXltFalsg%253D%253D&md5=57766c4eda06900a532375cd24c62476Diluted mainstream cigarette smoke condensates activate estrogen receptor and aryl hydrocarbon receptor-mediated gene transcriptionMeek, Murray D.; Finch, Gregory L.Environmental Research (1999), 80 (1), 9-17CODEN: ENVRAL; ISSN:0013-9351. (Academic Press)Epidemiol. data indicate that in females cigarette smoking exerts antiestrogenic effects that manifest clin. in an increased incidence of osteoporosis, earlier menopause, increased spot bleeding, and decreased risk of endometrial cancer for female smokers. The mol. mechanism of this effect is unclear; however, decreased serum estrogen levels in female smokers have been correlated with increased concns. of the metabolite 2-hydroxyestrogen in females who smoke. Induction of estrogen metabolizing enzymes, CYP1A1 and 1A2, is one mechanism by which increased 2-hydroxyestrogen concns. may occur. It has also been suggested that the estrogen receptor (ER) may contribute to this anti-estrogenic effect by binding to antagonist(s) in cigarette smoke. Gel retardation anal. was employed to det. if dild. mainstream cigarette smoke condensates (DMCSCs) could activate the aryl hydrocarbon receptor (AhR). AhR-regulated ethoxyresorufin-O-deethylase (EROD) activity and dioxin response element (DRE)-mediated luciferase induction were assessed in Hepa1c1c7 mouse hepatoma cells. A competitive ligand binding assay was utilized to det. if DMCSCs could bind to the ER. ER-dependent luciferase activity was assessed in MCF-7 cells. In gel retardation assays, DMCSCs induced a protein-DNA complex when incubated with a radiolabeled wild-type DRE oligonucleotide. The complex was effectively competed by excess unlabeled DRE but not by excess unlabeled mutant DRE. In Hepa1c1c7 mouse hepatoma cells transiently transfected with a DRE-regulated luciferase reporter gene, pGudluc1.1, treatment with DMCSCs resulted in a 23- and 25-fold increase in luciferase activity (P<0.01) and an 8.5- and 10.5-fold (P<0.01) induction in EROD activity, resp. DMCSCs completely displaced bound tritiated E2 from the ER in a dose-dependent manner and induced ER-regulated luciferase activity significantly 6-fold (P<0.01), representing 86% of the maximal induction obsd. with E2. DMCSCs can bind to and transcriptionally activate the AhR and ER nuclear receptors and cause induction of DRE- and ER-regulated genes. Further study is required to identify the specific compd.(s) responsible for these activities. (c) 1999 Academic Press.
- 23Bandow, N., Altenburger, R., Streck, G., and Brack, W. (2009) Effect-directed analysis of contaminated sediments with partition-based dosing using green algae cell multiplication inhibition. Environ. Sci. Technol. 43 (19), 7343– 7349, DOI: 10.1021/es901351z[ACS Full Text
], [CAS], Google Scholar23https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtVWqtrjL&md5=456ebfe19bd8b786ced79a8e68249237Effect-Directed Analysis of Contaminated Sediments with Partition-Based Dosing Using Green Algae Cell Multiplication InhibitionBandow, Nicole; Altenburger, Rolf; Streck, Georg; Brack, WernerEnvironmental Science & Technology (2009), 43 (19), 7343-7349CODEN: ESTHAG; ISSN:0013-936X. (American Chemical Society)Effect-directed anal. (EDA) has been frequently and successfully used to identify key toxicants in sediment exts. However, by disregarding bioavailability this approach may lead to a biased prioritization of fractions and toxicants with respect to hazards and risks. To overcome this problem, the present EDA of sediment components from the Bilina River (Most, Czech Republic), that inhibit growth of the green algae Scenedesmus vacuolatus, was applied as a novel partition-based dosing technique to prioritize and identify major toxic fractions and compds. in comparison to conventional solvent dosing. The novel dosing technique is based on partitioning from loaded silicone rods to the aq. phase similar to partition processes that det. exposure in native sediment-water systems. The application of partition-based dosing had a big influence suggesting polar compds. such as triclosan as key toxicants while polycyclic arom. hydrocarbon (PAH) fractions did not exhibit significant effects. In contrast, conventional dosing prioritized mainly PAHs in agreement with previous studies. For both approaches individual toxicants could be confirmed quant. based on the index of confirmation quality (ICQ), which compares the effect of fractions and artificial mixts. of identified and quantified toxicants over the full range of effect levels. - 24Thomas, K. V., Hurst, M. R., Matthiessen, P., Sheahan, D., and Williams, R. J. (2001) Toxicity characterisation of organic contaminants in stormwaters from an agricultural headwater stream in south east England. Water Res. 35 (10), 2411– 2416, DOI: 10.1016/S0043-1354(00)00535-2[Crossref], [PubMed], [CAS], Google Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXksVSqs7k%253D&md5=caa9fb00eebed457e37a92feb0a81701Toxicity characterization of organic contaminants in stormwaters from an agricultural headwater stream in South East EnglandThomas, K. V.; Hurst, M. R.; Matthiessen, P.; Sheahan, D.; Williams, R. J.Water Research (2001), 35 (10), 2411-2416CODEN: WATRAG; ISSN:0043-1354. (Elsevier Science Ltd.)The transient movement of pesticides at biol. active concns. during storm events is considered to be a cause of biol. impoverishment in some headwater streams. The program of work described sought to identify compds. that are the cause of toxic effects during such events. Along with targeted pesticide anal., toxicity identification evaluation (TIE) procedures were used to identify compds. with a demonstrated toxic effect. These procedures were specifically directed towards isolating and attributing toxicity to classes of org. contaminants in samples collected from an English headwater stream during a storm event. The org. load was isolated by solid-phase extn. (SPE). Bioassay of the SPE ext. at ×100 whole water concns. confirmed that the samples contained substances toxic to Daphnia magna, although the raw samples were not toxic. Targeted pesticide anal. identified simazine and diuron as the major pesticides present and, using a toxicity unit (TU) approach, were shown to be responsible for a significant amt. of the obsd. conc. toxicity during a runoff event. However, they were not present in sufficient quantities to be totally responsible for a more toxic later event. By simplification of the SPE isolate using reverse-phase HPLC, fractions from which were tested for toxicity, the cause of conc. toxicity in the later event was isolated to 2 discrete fractions. GC-MS anal. of these fractions identified nonylphenol (NP), endosulfan sulfate and pendimethalin as present, with the majority of toxicity attributed to NP. The main advantage of the TIE approach is that it allows biol. active compds. with a demonstrated effect to be identified that may not be selected by more traditional techniques.
- 25Thomas, K. V., Hurst, M. R., Matthiessen, P., and Waldock, M. J. (2001) Characterization of estrogenic compounds in water samples collected from United Kingdom estuaries. Environ. Toxicol. Chem. 20 (10), 2165– 2170, DOI: 10.1002/etc.5620201005[Crossref], [PubMed], [CAS], Google Scholar25https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XitlSqsQ%253D%253D&md5=d96085b03c92e92d67f7092154c871d3Characterization of estrogenic compounds in water samples collected from United Kingdom estuariesThomas, Kevin V.; Hurst, Mark R.; Matthiessen, Peter; Waldock, Mike J.Environmental Toxicology and Chemistry (2001), 20 (10), 2165-2170CODEN: ETOCDK; ISSN:0730-7268. (SETAC Press)This report describes the identification of important estrogenic compds. in surface and sediment pore-water samples from the Tyne and Tees estuaries (UK) through the application of toxicity identification evaluation (TIE) procedures. The Tyne and Tees estuaries represent estuaries that have been historically impacted by industrial activities and continue to receive treated domestic sewage and industrial effluent. In 1998, Dabholm Gut on the Tees received a mixt. of treated and untreated effluent, while Howdon sewage treatment works (STW) discharged primary treated effluents. An estrogenically active water sample collected from Howdon STW on the Tyne was shown to contain 17β-estradiol, androsterone, and an unknown estrogenic compds. Most of the activity contained in a sample collected from the Dabholm Gut combined discharges on the Tees was also due to 17β-estradiol with addnl. activity from nonylphenol and (tentatively) bis(2-ethylhexyl)phthalate. The only sediment pore-water sample to demonstrate estrogenic activity was from Dabholm Gut.
- 26Oda, Y., Nakamura, S. I., Oki, I., Kato, T., and Shinagawa, H. (1985) Evaluation of the new system (umu-test) for the detection of environmental mutagens and carcinogens. Mutat. Res.-Environ. Muta. 147 (5), 219– 229, DOI: 10.1016/0165-1161(85)90062-7[Crossref], [PubMed], [CAS], Google Scholar26https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL2MXlvFWhsbc%253D&md5=29763ba11ff7d1d1aaa282785d80e3c0Evaluation of the new system (umu test) for the detection of environmental mutagens and carcinogensOda, Yoshimitsu; Nakamura, Seiichi; Oki, Iwashiro; Kato, Takesi; Shinagawa, HideoMutation Research, Environmental Mutagenesis and Related Subjects (1985), 147 (5), 219-29CODEN: MEMSE8 ISSN:.The umu operon in Escherichia coli, responsible for chem. and radiation mutagenesis, and the expression of the operon itself is inducible by these DNA-damaging agents. The principle of the umu test is based on the ability of the DNA-damaging agents, most of which are potential carcinogens, to induce the umu operon. A plasmid (pSK1002) carrying a fused gene umuC'-'lacZ was introduced into Salmonella typhimurium TA 1535. The strain TA 1535/pSK1002 enabled the levels of umu operon expression to be monitored by measuring the β-galactosidase activity in the cells produced by the fusion gene. Using this strain, a simple, inexpensive, and sensitive system, the umu test, for the screening of environmental mutagens and carcinogens was developed. Chems. with different structures and modes of action, including 31 known animal carcinogens, were examd. by the test to evaluate the system. The threshold sensitivity of the umu test was approx. equal to the Ames test for chems. genotoxic in both tests. By the umu test, using the single tester strain, many types of DNA-damaging agents were detected for which the Ames test requires several tester strains. Furthermore, the umu test provides a potential practical advantage for the screening of various environmental samples contg. amino acids and nutrients such as urine, serum, and foods.
- 27Johnson, J. D., Houchens, D. P., Kluwe, W. M., Craig, D. K., and Fisher, G. L. (1990) Effects of mainstream and environmental tobacco smoke on the immune system in animals and humans: a review. Crit. Rev. Toxicol. 20 (5), 369– 395, DOI: 10.3109/10408449009089870[Crossref], [PubMed], [CAS], Google Scholar27https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK38Xnslyrtg%253D%253D&md5=b292a78ae84782a19599ceb6ff467449Effects of mainstream and environmental tobacco smoke on the immune system in animals and humans: a reviewJohnson, Jerry D.; Houchens, David P.; Kluwe, William M.; Craig, Douglas K.; Fisher, Gerald L.Critical Reviews in Toxicology (1990), 20 (5), 369-95CODEN: CRTXB2; ISSN:0045-6446.A review with 219 refs. of the available information on the effects of mainstream and environmental tobacco smoke on the immune system in animals and humans.
- 28Andreoli, C., Gigante, D., and Nunziata, A. (2003) A review of in vitro methods to assess the biological activity of tobacco smoke with the aim of reducing the toxicity of smoke. Toxicol. In Vitro 17 (5–6), 587– 594, DOI: 10.1016/S0887-2333(03)00091-2[Crossref], [PubMed], [CAS], Google Scholar28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXos12ls7c%253D&md5=989892aaf073a4975cf4133bf4d1e3dbA review of in vitro methods to assess the biological activity of tobacco smoke with the aim of reducing the toxicity of smokeAndreoli, Cristina; Gigante, Daniela; Nunziata, AlfredoToxicology in Vitro (2003), 17 (5/6), 587-594CODEN: TIVIEQ; ISSN:0887-2333. (Elsevier)A review. In the last few years tobacco companies were developing several research strategies to reduce the risks assocd. with smoking. These strategies include, for example, the refining of alternative cigarette designs that reduce the amt. of hazardous chems. in the mainstream smoke by introducing modified filters, and/or reducing the amt. of biol. significant ingredients in tobacco-burning cigarettes. In the last few decades numerous studies were published to assess the biol. activity of tobacco smoke using in vivo and in vitro test systems. In this scenario a general scientific consensus on how to measure and characterize the risk assocd. with cigarette smoke is still lacking. Short-term in vitro assays, which are widely accepted by regulatory agencies around the world, are useful tools to evaluate both the biol. activity and the progress towards a redn. of tobacco smoke toxicity. These assays could be mainly applied to evaluate cytotoxicity and genotoxicity properties on whole cigarette smoke as well as condensates or fractions of whole smoke. Cytotoxicity induction can be measured as cellular viability and growth rates using different end-points. Otherwise, the target of genotoxicity studies is the DNA mol. For genotoxicity evaluation, the end-points and cell systems should be chosen from those that are relevant and appropriate as clin. surrogate markers. In this respect, the occurrence of early biol. effect markers, such as mutational or clastogenic events (point mutations, frameshifts, micronuclei, SCE, DNA adducts) in bacterial and mammalian cells should be studied in a tiered approach following the guidelines of regulatory agencies. The choice of criteria shall be matter of discussion.
- 29(2012) Commission Implementing Regulation (EU) No 872/2012 of 1 October 2012 adopting the list of flavouring substances provided for by Regulation (EC) No 2232/96 of the European Parliament and of the Council, Introducing it in Annex I to Regulation (EC) No 1334/2008 of the European Parliament and of the Council and repealing Commission Regulation (EC) No 1565/2000 and Commission Decision 1999/217/EC Text with EEA relevance, European Commission, Brussels; https://eur-lex.europa.eu/legal-content/EN/TXT/HTML/?uri=CELEX:32012R0872&from=EN, accessed 5/1/2018.Google ScholarThere is no corresponding record for this reference.
- 30Wang, X., Liu, S., Xia, Q., Zhao, G., Guo, J., and Xie, F. (2013) Trace analysis of alkaline flavors in cut tobacco by heart-cutting multidimensional GC-GC-MS. J. Sep. Sci. 36 (23), 3750– 3757, DOI: 10.1002/jssc.201300836[Crossref], [PubMed], [CAS], Google Scholar30https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhs1WmtL%252FN&md5=c8ced2bc0f3d15344b4b060ea5f0442bTrace analysis of alkaline flavors in cut tobacco by heart-cutting multidimensional GC-GC-MSWang, Xiaoyu; Liu, Shaofeng; Xia, Qiaoling; Zhao, Ge; Guo, Jizhao; Xie, FuweiJournal of Separation Science (2013), 36 (23), 3750-3757CODEN: JSSCCJ; ISSN:1615-9306. (Wiley-VCH Verlag GmbH & Co. KGaA)Tobacco is a complex chem. matrix. The anal. of trace alk. flavors in tobacco is very difficult because of the limited peak capacity of monodimensional GC. In the present study, a home-assembled twin-oven GC-GC-MS system, with MS detection in both dimensions, has been applied to the anal. of 20 alk. volatiles in a variety of cut-tobacco samples. By transferring nine and six heart-cuts from the first apolar column to the second polar column in two sep. runs, the potential mutual interference of adjacent isomeric targets and the complex matrix could be removed. For comparative purposes, a systematic comparison of both quantification and qualification results for the cut-tobacco sample as quality control was conducted between GC-GC-MS and GC-MS. The results showed that GC-GC-MS provided higher accuracy in peak assignment and quantification. And in GC-MS, the interferences of co-elution had caused both low matched similarity in peak assignment and false-neg./-pos. results in quantification for some targets. Advantages of the developed GC-GC-MS method in the anal. of alk. flavors are its high resolving power, reliability, and simplicity.
- 31Moldoveanu, S. C. and St. Charles, F. K. (2007) Differences in the chemical composition of the particulate phase of inhaled and exhaled cigarette mainstream smoke. Beitr. Tab. Forsch. Int. 22 (4), 290– 302, DOI: 10.2478/cttr-2013-0834
- 32Brown, D. R., Clark, B. W., Garner, L. V., and Di Giulio, R. T. (2015) Zebrafish cardiotoxicity: the effects of CYP1A inhibition and AHR2 knockdown following exposure to weak aryl hydrocarbon receptor agonists. Environ. Sci. Pollut. Res. 22 (11), 8329– 8338, DOI: 10.1007/s11356-014-3969-2[Crossref], [PubMed], [CAS], Google Scholar32https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitFKmtbvN&md5=dee558b6c795cd102a63a5ea06d6b9daZebrafish cardiotoxicity: the effects of CYP1A inhibition and AHR2 knockdown following exposure to weak aryl hydrocarbon receptor agonistsBrown, Daniel R.; Clark, Bryan W.; Garner, Lindsey V. T.; Di Giulio, Richard T.Environmental Science and Pollution Research (2015), 22 (11), 8329-8338CODEN: ESPLEC; ISSN:0944-1344. (Springer)The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates many of the toxic effects of dioxin-like compds. (DLCs) and some polycyclic arom. hydrocarbons (PAHs). Strong AHR agonists, such as certain polychlorinated biphenyls and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), cause severe cardiac teratogenesis in fish embryos. Moderately strong AHR agonists, such as benzo[a]pyrene and β-naphthoflavone, have been shown to cause similar cardiotoxic effects when coupled with a cytochrome P 450 1A (CYP1A) inhibitor, such as fluoranthene (FL). We sought to det. if weak AHR agonists, when combined with a CYP1A inhibitor (FL) or CYP1A morpholino gene knockdown, are capable of causing cardiac deformities similar to moderately strong AHR agonists (Wassenberg and Di Giulio Environ Health Perspect 112(17):1658-1664, 2004a; Wassenberg and Di Giulio Res 58(2-5):163-168, 2004b; Billiard et al. Toxicol Sci 92(2):526-536, 2006; Van Tiem and Di Giulio Toxicol Appl Pharmacol 254(3):280-287, 2011). The weak AHR agonists included the following: carbaryl, phenanthrene, 2-methylindole, 3-methylindole, indigo, and indirubin. Danio rerio (zebrafish) embryos were first exposed to weak AHR agonists at equimolar concns. The agonists were assessed for their relative potency as inducers of CYP1 enzyme activity, measured by the ethoxyresorufin-O-deethylase (EROD) assay, and cardiac deformities. Carbaryl, 2-methylindole, and 3-methylindole induced the highest CYP1A activity in zebrafish. Expts. were then conducted to det. the individual cardiotoxicity of each compd. Next, zebrafish were coexposed to each agonist (at concns. below those detd. to be cardiotoxic) and FL in combination to assess if CYP1A inhibition could induce cardiac deformities. Carbaryl, 2-methylindole, 3-methylindole, and phenanthrene significantly increased pericardial edema relative to controls when combined with FL. To further evaluate the interaction of the weak AHR agonists and CYP1A inhibition, a morpholino was used to knockdown CYP1A expression, and embryos were then exposed to each agonist individually. In embryos exposed to 2-methylindole, CYP1A knockdown caused a similar level of pericardial edema to that caused by exposure to 2-methylindole and FL. The results showed a complex pattern of cardiotoxic response to weak agonist inhibitor exposure and morpholino-knockdown. However, CYP1A knockdown in phenanthrene and 3-methylindole only moderately increased pericardial edema relative to coexposure to FL. AHR2 expression was also knocked down using a morpholino to det. its role in mediating the obsd. cardiac teratogenesis. Knockdown of AHR2 did not rescue the pericardial edema as previously obsd. with strong AHR agonists. While some of the cardiotoxicity obsd. may be attributed to the combination of weak AHR agonism and CYP1A inhibition, other weak AHR agonists appear to be causing cardiotoxicity through an AHR2-independent mechanism. The data show that CYP1A is protective of the cardiac toxicity assocd. with weak AHR agonists and that knockdown can generate pericardial edema, but these findings are also suggestive of differing mechanisms of cardiac toxicity among known AHR agonists.
- 33Sovadinová, I., Bláha, L., Janošek, J., Hilscherová, K., Giesy, J. P., Jones, P. D., and Holoubek, I. (2006) Cytotoxicity and aryl hydrocarbon receptor-mediated activity of N-heterocyclic polycyclic aromatic hydrocarbons: Structure-activity relationships. Environ. Toxicol. Chem. 25 (5), 1291– 1297, DOI: 10.1897/05-388R.1[Crossref], [PubMed], [CAS], Google Scholar33https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XktlGjs7k%253D&md5=7e513326bad8e7eea128157c1b8fc503Cytotoxicity and aryl hydrocarbon receptor-mediated activity of N-heterocyclic polycyclic aromatic hydrocarbons: structure-activity relationshipsSovadinova, Iva; Blaha, Ludek; Janosek, Jaroslav; Hilscherova, Klara; Giesy, John P.; Jones, Paul D.; Holoubek, IvanEnvironmental Toxicology and Chemistry (2006), 25 (5), 1291-1297CODEN: ETOCDK; ISSN:0730-7268. (SETAC Press)Toxic effects of many persistent org. pollutants (e.g., polychlorinated biphenyls or polychlorinated dibenzo-p-dioxins and furans) are mediated via the aryl hydrocarbon receptor (AhR). Although polycyclic arom. hydrocarbons (PAHs) and their derivs. also activate AhR, their toxic effects remain to be fully elucidated. In the present study, the authors used the in vitro H4IIE-luc transactivation cell assay to investigate cytotoxicity and potencies to activate AhR by 29 individual PAHs and their N-heterocyclic derivs. (aza-PAHs). The aza-PAHs were found to be significantly more cytotoxic and more potent inducers of AhR than their unsubstituted analogs. Several aza-PAHs, such as dibenz[a,h]acridine or dibenz[a,i]acridine, activated AhR within picomolar concns., comparable to the effects of ref. 2,3,7,8-tetrachlorodibenzo-p-dioxin. Ellipsoidal vol., molar refractivity, and mol. size were the most important descriptors derived from the modeling of quant. structure-activity relationships for potencies to activate AhR. Comparable relative toxic potencies (induction equivalency factors) for individual aza-PAHs are derived, and their use for evaluation of complex contaminated samples is discussed.
- 34Hubbard, T. D., Murray, I. A., Bisson, W. H., Lahoti, T. S., Gowda, K., Amin, S. G., Patterson, A. D., and Perdew, G. H. (2015) Adaptation of the human aryl hydrocarbon receptor to sense microbiota-derived indoles. Sci. Rep. 5, 12689, DOI: 10.1038/srep12689[Crossref], [PubMed], [CAS], Google Scholar34https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsVKiurvL&md5=3983f2dfc263478b56331e93bd0e8d90Adaptation of the human aryl hydrocarbon receptor to sense microbiota-derived indolesHubbard, Troy D.; Murray, Iain A.; Bisson, William H.; Lahoti, Tejas S.; Gowda, Krishne; Amin, Shantu G.; Patterson, Andrew D.; Perdew, Gary H.Scientific Reports (2015), 5 (), 12689CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)Ligand activation of the aryl hydrocarbon (AHR) has profound effects upon the immunol. status of the gastrointestinal tract, establishing and maintaining signaling networks, which facilitate host-microbe homeostasis at the mucosal interface. However, the identity of the ligand(s) responsible for such AHR-mediated activation within the gut remains to be firmly established. Here, we combine in vitro ligand binding, quant. gene expression, protein-DNA interaction and ligand structure activity analyses together with in silico modeling of the AHR ligand binding domain to identify indole, a microbial tryptophan metabolite, as a human-AHR selective agonist. Human AHR, acting as a host indole receptor may exhibit a unique bimol. (2:1) binding stoichiometry not obsd. with typical AHR ligands. Such bimol. indole-mediated activation of the human AHR within the gastrointestinal tract may provide a foundation for inter-kingdom signaling between the enteric microflora and the immune system to promote commensalism within the gut.
- 35Stepankova, M., Bartonkova, I., Jiskrova, E., Vrzal, R., Mani, S., Kortagere, S., and Dvorak, Z. (2018) Methylindoles and methoxyindoles are agonists and antagonists of human aryl hydrocarbon receptor. Mol. Pharmacol. 93, 631– 644, DOI: 10.1124/mol.118.112151[Crossref], [PubMed], [CAS], Google Scholar35https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhslOnu7rK&md5=053972ffe1b5cb356823c2a572b5f4f0Methylindoles and methoxyindoles are agonists and antagonists of human aryl hydrocarbon receptorStepankova, Martina; Bartonkova, Iveta; Jiskrova, Eva; Vrzal, Radim; Mani, Sridhar; Kortagere, Sandhya; Dvorak, ZdenekMolecular Pharmacology (2018), 93 (6), 631-644CODEN: MOPMA3; ISSN:1521-0111. (American Society for Pharmacology and Experimental Therapeutics)Novel methylindoles were identified as endobiotic and xenobi- otic ligands of the human aryl hydrocarbon receptor (AhR). We examd. the effects of 22 methylated and methoxylated indoles on the transcriptional activity of AhRs. Employing reporter gene assays in AZ-AHR transgenic cells, we detd. full agonist, partial agonist, or antagonist activities of tested compds., having substantially variable EC50, IC50, and relative efficacies. The most effective agonists (EMAX relative to 5 nM dioxin) of the AhR were 4-Me-indole (134%), 6-Me-indole (91%), and 7-MeO- indole (80%), resp. The most effective antagonists of the AhR included 3-Me-indole (IC50; 19 μM), 2,3-diMe-indole (IC50; 11 μM), and 2,3,7-triMe-indole (IC50; 12 μM). Reverse transcrip- tion polymerase chain reaction analyses of CYP1A1 mRNA in LS180 cells confirmed the data from gene reporter assays. The compd. leads, 4-Me-indole and 7-MeO-indole, induced sub- stantial nuclear translocation of the AhR and enriched binding of the AhR to the CYP1A1 promoter, as obsd. using fluores- cent immunohistochem. and chromatin immunopptn. assays, resp. Mol. modeling and docking studies suggest the agonists and antagonists likely share the same binding pocket but have unique binding modes that code for their affinity. Binding pocket anal. further revealed that 4-methylindole and 7-methoxyindole can simultaneously bind to the pocket and produce synergistic interactions. Together, these data show a dependence on subtle and specific chem. indole structures as AhR modulators and furthermore under- score the importance of complete evaluation of indole com- pounds as nuclear receptor ligands.
- 36(2018) Phthalates, U.S. Food and Drug Administration, Silver Spring, MD. https://www.fda.gov/Cosmetics/ProductsIngredients/Ingredients/ucm128250.htm (accessed June 27, 2019).Google ScholarThere is no corresponding record for this reference.
- 37Liu, Q., Chen, D., Wu, J., Yin, G., Lin, Q., Zhang, M., and Hu, H. (2018) Determination of phthalate esters in soil using a quick, easy, cheap, effective, rugged, and safe method followed by GC-MS. J. Sep. Sci. 41 (8), 1812– 1820, DOI: 10.1002/jssc.201701126[Crossref], [PubMed], [CAS], Google Scholar37https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisFektbo%253D&md5=d4c4042ab50727b0a7ff16663aaafe9aDetermination of phthalate esters in soil using a quick, easy, cheap, effective, rugged, and safe method followed by GC-MSLiu, Qianjun; Chen, Di; Wu, Jiyuan; Yin, Guangcai; Lin, Qintie; Zhang, Min; Hu, HuawenJournal of Separation Science (2018), 41 (8), 1812-1820CODEN: JSSCCJ; ISSN:1615-9314. (Wiley-VCH Verlag GmbH & Co. KGaA)A quick, easy, cheap, effective, rugged, and safe procedure was designed to ext. pesticide residues from fruits and vegetables with a high percentage of water. It has not been used extensively for the extn. of phthalate esters from sediments, soils, and sludges. In this work, this procedure was combined with gas chromatog. with mass spectrometry to det. 16 selected phthalate esters in soil. The extn. efficiency of the samples was improved by ultrasonic extn. and dissoln. of the soil samples in ultra-pure water, which promoted the dispersion of the samples. Furthermore, we have simplified the extn. step and reduced the risk of org. solvent contamination by minimizing the use of org. solvents. Different extn. solvents and clean-up adsorbents were compared to optimize the procedure. Dichloromethane/n-hexane (1:1, vol./vol.) and n-hexane/acetone (1:1, vol./vol.) were selected as the extractants from the six extn. solvents tested. C18/primary secondary amine (1:1, m/m) was selected as the sorbent from the five clean-up adsorbents tested. The recoveries from the spiked soils ranged from 70.00 to 117.90% with relative std. deviation values of 0.67-4.62%. The proposed approach was satisfactorily applied for the detn. of phthalate esters in 12 contaminated soil samples.
- 38Zhu, F., Mao, C., and Du, D. (2017) Time-resolved immunoassay based on magnetic particles for the detection of diethyl phthalate in environmental water samples. Sci. Total Environ. 601, 723– 731, DOI: 10.1016/j.scitotenv.2017.05.111[Crossref], [PubMed], [CAS], Google Scholar38https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXpt12lt7o%253D&md5=174d2024699aefb1de48f956dfdb2902Time-resolved immunoassay based on magnetic particles for the detection of diethyl phthalate in environmental water samplesZhu, Fang; Mao, Chaoming; Du, DaolinScience of the Total Environment (2017), 601-602 (), 723-731CODEN: STENDL; ISSN:0048-9697. (Elsevier B.V.)Di-Et phthalate (DEP) is an extensively used phthalic acid diester (PAEs) with estrogenic activity and the potential for carcinogenic and teratogenic effects. To monitor trace DEP in environmental waters, a sensitive direct competitive time-resolved fluoroimmunoassay based on magnetic particles (MPs) as solid support was established. For the assay system, the anti-DEP antibody was oriented on the surface of the MPs using goat anti-rabbit antibody as linkers, and DEP-OVA was labeled using Eu3 +. Several physicochem. factors that potentially influence the assay performance of the proposed method were studied in detail, including concn. of MPs, diln. of DEP-OVA-Eu3 + and incubation time. Under the optimized conditions, the method showed: (i) low limit of detection (LOD) of 5.92 ng/L; (ii) satisfactory accuracy (recoveries, 91.97-134.54%) with good reproducibility (inter-CV, 4.17-9.17%; intra-CV, 7.41-14.72%). All of which indicated that the newly established method had much higher efficiency and great potential for use in environmental water anal. for DEP. In addn., the proposed immunoassay was applied for study of DEP in aquatic environments at Zhenjiang City. The authors' results showed that DEP was detected at the concn. of 2.98-65.18 ng/mL in river samples and 46.95-306.19 ng/mL in wastewater treatment plants (WWTPs), which showed rather high concns. compared with reported data. The authors' study provides background data important for risk assessment and contamination control of DEP in the aquatic environment of this area.
- 39Kadi, M. W., Ali, N., and Albar, H. M. S. A. (2018) Phthalates and polycyclic aromatic hydrocarbons (PAHs) in the indoor settled carpet dust of mosques, health risk assessment for public. Sci. Total Environ. 627, 134– 140, DOI: 10.1016/j.scitotenv.2018.01.146[Crossref], [PubMed], [CAS], Google Scholar39https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitFygu7s%253D&md5=def428f8fffa31ade249fd284d6844f0Phthalates and polycyclic aromatic hydrocarbons (PAHs) in the indoor settled carpet dust of mosques, health risk assessment for publicKadi, Mohammad W.; Ali, Nadeem; Albar, Hussain Mohammed Salem AliScience of the Total Environment (2018), 627 (), 134-140CODEN: STENDL; ISSN:0048-9697. (Elsevier B.V.)A no. of studies have reported the occurrence of phthalates and polycyclic arom. hydrocarbons (PAHs) in indoor settled dust from different occupational and residential settings around the world but limited studies are available from public and religious places. In recent decades Kingdom of Saudi Arabia (KSA) has experienced tremendous industrial growth esp. in the petroleum industries, and as result environmental issues related with such industries have also increased but scientific data is still scarce to understand the impact on public health. Therefore, the main objective of this study was to report the phthalates and PAHs profile in the settled dust collected from various mosques of Jeddah, an important part of people living in the region, and to evaluate the health risk assocd. with these chems. via dust ingestion, inhalation and dermal contact for the general public who attend mosques for prayers. Phenanthrene (500-3000ng/g), pyrene (40-1220ng/g), and chrysene (95-4590ng/g) were the major PAHs and .sum.12PAHs concns. ranged from 2550 to 9150ng/g. Whereas, DEHP (<LOQ-292900 ng/g) and BzBP (<LOQ-292900 ng/g) were the major phthalates in the mosque dust. Health risk assessment for the public was calcd. by incremental lifetime cancer risk (ILCR), and daily exposure to via dust ingestion, inhalation, and dermal contact for both PAHs and phthalates. At the same time, benzo[a]pyrene equiv. carcinogenic power (BaPE) (median 145ng/g) was calcd. for PAHs. The ILCR for PAHs was in line with the ref. values of USEPA. At the same time, exposure via dust ingestion on daily basis reached up to 82ng/kg bw/day for DEHP for young children. The study showed general public is exposed to these chems. in the studied area and major exposure routes are dermal and ingestion.
- 40(2012). Endocrine Disruptor Screening Program (EDSP) Universe of Chemicals, U.S. Environmental Protection Agency, Washington, DC.Google ScholarThere is no corresponding record for this reference.
- 41Mankidy, R., Wiseman, S., Ma, H., and Giesy, J. P. (2013) Biological impact of phthalates. Toxicol. Lett. 217 (1), 50– 58, DOI: 10.1016/j.toxlet.2012.11.025[Crossref], [PubMed], [CAS], Google Scholar41https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXnvFCmsg%253D%253D&md5=3f2b6ee66eec606999c90c703cbebda6Biological impact of phthalatesMankidy, Rishikesh; Wiseman, Steve; Ma, Hong; Giesy, John P.Toxicology Letters (2013), 217 (1), 50-58CODEN: TOLED5; ISSN:0378-4274. (Elsevier Ireland Ltd.)Esters of phthalic acid are chem. agents used to improve the plasticity of industrial polymers. Their ubiquitous use in multiple com. products results in extensive exposure to humans and the environment. This study investigated cytotoxicity, endocrine disruption, effects mediated via AhR, lipid peroxidn. and effects on expression of enzymes of xenobiotic metab. caused by di-(2-ethy hexyl) phthalate (DEHP), di-Et phthalate (DEP), di-Bu phthalate (DBP) and benzyl Bu phthalate (BBP) in developing fish embryos. Oxidative stress was identified as the crit. mechanism of toxicity (CMTA) in the case of DEHP and DEP, while the efficient removal of DBP and BBP by phase 1 enzymes resulted in lesser toxicity. DEHP and DEP did not mimic estradiol (E2) in transactivation studies, but at concns. of 10 mg/L synthesis of sex steroid hormones was affected. Exposure to 10 mg BBP/L resulted in weak transactivation of the estrogen receptor (ER). All phthalates exhibited weak potency as agonists of the aryl hydrocarbon receptor (AhR). The order of potency of the 4 phthalates studied was; DEHP > DEP > BBP > > DBP. The study highlights the need for simultaneous assessment of: multiple cellular targets affected by phthalates and phthalate mixts. to account for additive effects when multiple phthalates modulate the same pathway. Such cumulative assessment of multiple biol. parameters is more realistic, and offers the possibility of more accurately identifying the CMTA.
- 42Harris, C. A., Henttu, P., Parker, M. G., and Sumpter, J. P. (1997) The estrogenic activity of phthalate esters in vitro. Environ. Health Perspect. 105 (8), 802, DOI: 10.1289/ehp.97105802[Crossref], [CAS], Google Scholar42https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXnt1GjurY%253D&md5=735feeb0cad72ea9168208dc1fe8c28eThe estrogenic activity of phthalate esters in vitroHarris, Catherine A.; Henttu, Pirkko; Parker, Malcolm G.; Sumpter, John P.Environmental Health Perspectives (1997), 105 (8), 802-811CODEN: EVHPAZ; ISSN:0091-6765. (National Institute of Environmental Health Sciences)A large no. of phthalate esters were screened for estrogenic activity using a recombinant yeast screen. A selection of these was also tested for mitogenic effect on estrogen-responsive human breast cancer cells. A small no. of the com. available phthalates tested showed extremely weak estrogenic activity. The relative potencies of these descended in the order Bu benzyl phthalate (BBP)>dibutyl phthalate (DBP)>diisobutyl phthalate (DIBP)>diethyl phthalate (DEP)>diisononyl phthalate (DINP). Potencies ranged from approx. 1 × 106 to 5 × 107 times less than 17β-estradiol. The phthalates that were estrogenic in the yeast screen were also mitogenic on the human breast cancer cells. Di(2-ethylhexyl) phthalate (DEHP) showed no estrogenic activity in these in vitro assays. A no. of metabolites were tested, including mono-Bu phthalate, mono-benzyl phthalate, mono-ethylhexyl phthalate, mono-n-octyl phthalate; all were found to be inactive. One of the phthalates, ditridecyl phthalate (DTDP), produced inconsistent results; one sample was weakly estrogenic, whereas another, obtained from a different source, was inactive. Anal. by gel chromatog.-mass spectrometry showed that the prepn. exhibiting estrogenic activity contained 0.5% of the ortho-isomer of bisphenol A. It is likely that the presence of this antioxidant in the phthalate std. was responsible for the generation of a dose-response curve-which was not obsd. with an alternative sample that had not been supplemented with o,p'-bisphenol A-in the yeast screen; hence, DTDP is probably not weakly estrogenic. The activities of simple mixts. of BBP, DBP, and 17β-estradiol were assessed in the yeast screen. No synergism was obsd., although the activities of the mixts. were approx. additive. In summary, a small no. of phthalates are weakly estrogenic in vitro. No data has yet been published on whether these are also estrogenic in vivo; this will require tests using different classes of vertebrates and different routes of exposure.
- 43Kumar, N., Sharan, S., Srivastava, S., and Roy, P. (2014) Assessment of estrogenic potential of diethyl phthalate in female reproductive system involving both genomic and non-genomic actions. Reprod. Toxicol. 49, 12– 26, DOI: 10.1016/j.reprotox.2014.06.008[Crossref], [PubMed], [CAS], Google Scholar43https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXht1Ojs7vO&md5=e5097492c564bfa86469c0f5fb742371Assessment of estrogenic potential of diethyl phthalate in female reproductive system involving both genomic and non-genomic actionsKumar, Narender; Sharan, Shruti; Srivastava, Swati; Roy, ParthaReproductive Toxicology (2014), 49 (), 12-26CODEN: REPTED; ISSN:0890-6238. (Elsevier Inc.)Phthalates are the diverse group of compds. abundantly present in environment. The present study shows the estrogenic potential of di-Et phthalate (DEP). The data showed that DEP increased the transactivation of ER in CHO and MCF-7 cells suggesting its interaction with ER. In vivo parameters like increased uterine epithelial cell height and up regulation of various steroidogenic genes were also obsd. in adult female rats. Our uterotrophic assay data from immature female rats suggested that DEP treatment resulted in augmentation of uterine wt. as well as luminal epithelial cell heights in both vaginal and uterine tissues. Further, DEP was able to upregulate pS2 gene expression with simultaneous activation of MAPK pathway as demonstrated by increased p-ERK/ERK ratio. Taken together, the present data suggests that DEP acts as an estrogenic compd. and based on these data further detailed studies would reveal its mode of action at cellular levels.
- 44Akalin, M. K. and Karagoz, S. (2011) Pyrolysis of tobacco residue: part 1. Thermal. BioResources 6 (2), 1520– 1531Google ScholarThere is no corresponding record for this reference.
- 45Yin, C., Xu, Z., Shu, J., Wang, H., Li, Y., Sun, W., Zhou, Z., Chen, M., and Zhong, F. (2014) Study on the effect of potassium lactate additive on the combustion behavior and mainstream smoke of cigarettes. J. Therm. Anal. Calorim. 115 (2), 1733– 1751, DOI: 10.1007/s10973-013-3478-4[Crossref], [CAS], Google Scholar45https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhslWisrzO&md5=4c54211783d3f6d2f4c3165c1e264909Study on the effect of potassium lactate additive on the combustion behavior and mainstream smoke of cigarettesYin, Chunyan; Xu, Zhiqiang; Shu, Junsheng; Wang, Hua; Li, Yue; Sun, Weifeng; Zhou, Zhilei; Chen, Maoshen; Zhong, FangJournal of Thermal Analysis and Calorimetry (2014), 115 (2), 1733-1751CODEN: JTACF7; ISSN:1388-6150. (Springer)The influence of potassium lactate (PL) on the combustion behavior and semi-volatile compds. of tobacco during smoking is investigated in this study. The addn. of PL showed no effect on the content of total particulate matter, nicotine-free dry particulate matter, puff no., and nicotine. Meanwhile, a 22.5 % increase in moisture content and 3 % decrease in CO content of mainstream smoke were obsd. when the added amt. of PL was up to 2 %. The differential thermogravimetric curves indicated that PL decreased the max. combustion rate and influenced the thermal degrdn. stage of tobacco by shifting the peak point of temp. to a higher value. The gas evolution profiles obtained from Fourier transform IR spectroscopy during combustion showed that PL could lower the CO and CO2 yield, but did not affect the generation of CH4 and carbonyl compds. A great variation in semi-volatile components of the mainstream smoke was also obsd. from the tobacco contg. PL compared with the control. The comprehensive two-dimensional gas chromatog. coupled to time-of-flight mass spectrometry anal. showed that PL increased the yield of alcs., lactons, misc. oxygenated compds. and amides, but decreased that of aldehydes, acids, pyrroles and pyrazines. A small added amt. (0.2 %) of PL reduced the content of total semi-volatile substances, ketones, esters, phenols, hydrocarbons, pyridines, tobacco alkaloids, and nitrogenous compd. However, the contents of these substances were not affected when the added amt. was >0.2 %. PL bound the ash during combustion, thereby leading to the change of combustion behavior and certain smoke components.
- 46Stabbert, R., Dempsey, R., Diekmann, J., Euchenhofer, C., Hagemeister, T., Haussmann, H. J., Knorr, A., Mueller, B. P., Pospisil, P., Reininghaus, W., Roemer, E. (2017) Studies on the contributions of smoke constituents, individually and in mixtures, in a range of in vitro bioactivity assays. Toxicol. In Vitro 42, 222– 246, DOI: 10.1016/j.tiv.2017.04.003[Crossref], [PubMed], [CAS], Google Scholar46https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXnsVart74%253D&md5=65be46f8eaa06e604a0fcd2c3c4a9083Studies on the contributions of smoke constituents, individually and in mixtures, in a range of in vitro bioactivity assaysStabbert, Regina; Dempsey, Ruth; Diekmann, Joerg; Euchenhofer, Christian; Hagemeister, Timo; Haussmann, Hans-Juergen; Knorr, Arno; Mueller, Boris P.; Pospisil, Pavel; Reininghaus, Wolf; Roemer, Ewald; Tewes, Franz J.; Veltel, Detlef J.Toxicology In Vitro (2017), 42 (), 222-246CODEN: TIVIEQ; ISSN:0887-2333. (Elsevier Ltd.)Tobacco smoke is a complex mixt. with over 8700 identified constituents. Smoking causes many diseases including lung cancer, cardiovascular disease, and chronic obstructive pulmonary disease. However, the mechanisms of how cigarette smoke impacts disease initiation or progression are not well understood and individual smoke constituents causing these effects are not generally agreed upon. The studies reported here were part of a series of investigations into the contributions of selected smoke constituents to the biol. activity of cigarette smoke. In vitro cytotoxicity measured by the neutral red uptake (NRU) assay and in vitro mutagenicity detd. in the Ames bacterial mutagenicity assay (BMA) were selected because these assays are known to produce reproducible, quant. for cigarette smoke under standardized exposure conditions. To det. the contribution of individual cigarette smoke constituents, a fingerprinting method was developed to semi-quantify the mainstream smoke yields. For cytotoxicity, 90% of gas vapor phase (GVP) cytotoxicity of the Kentucky Ref. cigarette 1R4F was explained by 3 aldehydes and 40% of the 1R4F particulate phase cytotoxicity by 10 smoke constituents, e.g., hydroquinone. In the microsuspension version of the BMA, 4 aldehydes accounted for approx. 70% of the GVP mutagenicity. Finally, the benefits of performing such studies along with the difficulties in interpretation in the context of smoking are discussed.
- 47Wright, S. L., Rowe, D., Reid, M. J., Thomas, K. V., and Galloway, T. S. (2015) Bioaccumulation and biological effects of cigarette litter in marine worms. Sci. Rep. 5, 14119, DOI: 10.1038/srep14119[Crossref], [PubMed], [CAS], Google Scholar47https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsFeis7zP&md5=94ccd4df76ee309bb079604728c88c66Bioaccumulation and biological effects of cigarette litter in marine wormsWright, Stephanie L.; Rowe, Darren; Reid, Malcolm J.; Thomas, Kevin V.; Galloway, Tamara S.Scientific Reports (2015), 5 (), 14119CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)Marine debris is a global environmental issue. Smoked cigarette filters are the predominant coastal litter item; 4.5 trillion are littered annually, presenting a source of bioplastic microfibres (cellulose acetate) and harmful toxicants to marine environments. Despite the human health risks assocd. with smoking, little is known of the hazards cigarette filters present to marine life. Here we studied the impacts of smoked cigarette filter toxicants and microfibres on the polychaete worm Hediste diversicolor (ragworm), a widespread inhabitant of coastal sediments. Ragworms exposed to smoked cigarette filter toxicants in seawater at concns. 60 fold lower than those reported for urban run-off exhibited significantly longer burrowing times, >30% wt. loss, and >2-fold increase in DNA damage compared to ragworms maintained in control conditions. In contrast, ragworms exposed to smoked cigarette filter microfibres in marine sediment showed no significant effects. Bioconcn. factors for nicotine were 500 fold higher from seawater than from sediment. Our results illustrate the vulnerability of organisms in the water column to smoking debris and assocd. toxicants, and highlight the risks posed by smoked cigarette filter debris to aquatic life.
- 48Benowitz, N. L., Hukkanen, J., and Jacob, P. (2009). Nicotine chemistry, metabolism, kinetics and biomarkers. In Nicotine psychopharmacology, pp 29– 60, Springer, Berlin, Heidelberg.
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- Cuong D. Tran, Nathan G. Dodder, Penelope J.E. Quintana, Kayo Watanabe, Jae H. Kim, Melbourne F. Hovell, Christina D. Chambers, Eunha Hoh. Organic contaminants in human breast milk identified by non-targeted analysis. Chemosphere 2020, 238, 124677. DOI: 10.1016/j.chemosphere.2019.124677.
Abstract

Figure 1

Figure 1. (a) Overall experimental design. SCL was tested in vitro for toxicity, estrogen receptor, AhR, and p53 response. SCL was then separated into fractions by polarity and retested in assays that exhibited a positive response during initial toxicological testing. Following testing of SCL fractions, the nontargeted chemical analysis was performed to identify compounds potentially responsible for biological response. (b) Steps of chemical data analysis. Nontargeted chemical analysis of SCL was conducted to isolate all compounds uniquely found in SCL fractions that exhibited biological response. All compounds were first screened for their absence in control samples and compiled into a preliminary list of potential compounds. Compounds from the preliminary list were then organized by the SCL fractions in which they were found. Compounds found only in fractions exhibiting biological response were then considered for confirmation with an authentic reference standard.
Figure 2

Figure 2. Cytotoxicity of 10 cig/L, 100 cig/L, and SPE-extracted 100 cig/L SCL samples in (a, b) AhR cells, (c) ER cells, and (d) p53 cells. Mean ± SD, n = 3. FW, freshwater; SW, seawater; and SPE, solid-phase extracted sample. Number n in the sample code indicates dilution of 2n times (dilution factors range from 2 to 64).
Figure 3

Figure 3. Bioactivities of 10 cig/L, 100 cig/L, and SPE-extracted 100 cig/L SCL samples. (a) RLU of E2 and samples, (b) blue/green ratio of PCB126 and samples, and (c) blue/green ratio of mitomycin and samples. The horizontal dotted line in (a–c) indicates the benchmark of activity. SW, seawater; FW, freshwater; 10cig, 10 cig/L sample; 100cig, 100 cig/L sample; and SPE, solid-phase extracted sample. Triangles represent seawater tests and circles represent freshwater tests. (d) The mean aryl hydrocarbon toxicity equivalents (TEQ) of fractionated (eluted by 10%, 25%, 50%, 75%, and 100% MeOH/H2O in order or 100% MeOH only) seawater and freshwater SCL samples (mean ± SD, n = 3).
Figure 4

Figure 4. Genotoxicity of fractionated SCL samples. IR was calculated as a quantitative measure of the genotoxicity of fractionated samples. For each sample dilution, β-galactosidase activity and growth factor were combined to form the IR. SW samples showed higher IRs than FW samples, but the growth factors were below 0.5 for all samples, suggesting their negligible genotoxicity. FW, freshwater; SW, seawater; SPE, solid-phase extracted sample. Mean ± SD, n = 3.
Figure 5

Figure 5. Peak true mass spectra of the five identifiable compounds and their matching mass spectra in the NIST database.
Figure 6

Figure 6. Cytotoxicity (left) and AhR activity (right) of 2-MI expressed as relative cell availability and blue/green ratio, respectively. Mean ± SD, n = 3.
References
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- 15Lee, W. and Lee, C. C. (2015) Developmental toxicity of cigarette butts-An underdeveloped issue. Ecotoxicol. Environ. Saf. 113, 362– 368, DOI: 10.1016/j.ecoenv.2014.12.018[Crossref], [PubMed], [CAS], Google Scholar15https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXlvFOntQ%253D%253D&md5=e53fac2a7716d1bfdf8314561bd2bfceDevelopmental toxicity of cigarette butts - An underdeveloped issueLee, Wenjau; Lee, Chih ChunEcotoxicology and Environmental Safety (2015), 113 (), 362-368CODEN: EESADV; ISSN:0147-6513. (Elsevier B.V.)Cigarette butts (CBs) littering is not just an unsightly nuisance but also a public health problem, because chems. contained in cigarettes can leach into aquatic environments and pose a risk to the health of humans and wildlife. However, this risk is largely unrecognized or ignored by the public, and toxicol. evidence of CBs is scarce. Therefore, we used medaka embryos (Oryzias latipes) to explore developmental toxicity of CBs. The embryos were exposed to various concns. of leachates from smoked and unsmoked cigarette tobacco (ST and UST) and filters (SF and USF), and obsd. from 1 to 3 days post-fertilization. The images were recorded and several developmental endpoints analyzed. The values from these endpoints were then used to calc. the Integrated Biomarker Response and evaluate overall effects of the leachates. Some of the embryos were allowed to hatch, and the hatchlings were tested for anxiety-like behavior. Our results showed that low concns. of the leachates from ST, UST, and SF raised the heart rate, accelerated development, and changed behavior, while high concns. lowered the heart rate, suppressed development, and increased mortality. The lowest obsd. effect concn. for the leachates was ≤0.2 piece (pc)/L. The USF leachate had no effect at the concn. of 20 pc/L. Developmental toxicity of the leachates was ranked as: ST>UST>SF>USF. This study has demonstrated for the first time that CB leachates affect fish development, and provided toxicol. evidence to better assess ecol. impacts of CBs.
- 16(1988) The Health Consequences of Smoking: Nicotine Addiction, A Report of the Surgeon General, U.S. Department of Health and Human Services, Rockville, MD. https://profiles.nlm.nih.gov/ps/access/nnbbzd.pdf (accessed June 27, 2019).Google ScholarThere is no corresponding record for this reference.
- 17Begum, A. N., Aguilar, J. S., and Hong, Y. (2017) Aqueous cigarette tar extracts disrupt corticogenesis from human embryonic stem cells in vitro. Environ. Res. 158, 194– 202, DOI: 10.1016/j.envres.2017.06.012[Crossref], [PubMed], [CAS], Google Scholar17https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtVKgu7zI&md5=1822527c875a4a8da982e4baea1cdeefAqueous cigarette tar extracts disrupt corticogenesis from human embryonic stem cells in vitroBegum, Aynun N.; Aguilar, Jose S.; Hong, YilingEnvironmental Research (2017), 158 (), 194-202CODEN: ENVRAL; ISSN:0013-9351. (Elsevier)Cigarette butts are the most common form of litter in the world, and approx. 4.5 trillion smoked cigarettes are discarded every year worldwide. Cigarette butts contain over 4000 chems., many of which are known to have neurotoxic effects. Stem cell neuronal differentiation provides an excellent cellular model with which to examine the impact of aq. cigarette tar exts. (ACTEs) on neurodevelopment. We have developed a neurosphere-based stem cell neuronal differentiation protocol that can recapitulate corticogenesis and produce cell types that are similar to upper and lower layer cortical projection neurons found in the germinal zone of the developing human cortex. In this study, ACTEs were generated from smoked cigarette butts and then applied at different concns. to neuronal progenitors and cortical neurons derived from human embryonic stem cells. ACTEs reduced the expression of the cortical neuronal progenitor markers pax6, tbr2, and neuroD and decreased the no. of cortical layer neurons (tbr1, satb2, foxp2, and brn2) after exposure to as low as 1.87% of the ext. from one smoked cigarette butt. Furthermore, our results showed that ACTEs increased reactive oxygen species (ROS) prodn. in cortical neurons, which caused a substantial loss of the synaptic proteins PSD95, synaptophysin, vesicular glutamate transporter1 (vGlut1), and the extracellular matrix mol. reelin; all of those mols. are important for the maintenance of cortical neuron identity and activity. ACTEs from smoked cigarettes have significant effects on cortical neuron development and neurodegeneration. The stem cell neuronal differentiation model holds great promise as a potentially powerful tool for the assessment of ACTEs on neurotoxicity.
- 18Denison, M. S. and Nagy, S. R. (2003) Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals. Annu. Rev. Pharmacol. Toxicol. 43 (1), 309– 334, DOI: 10.1146/annurev.pharmtox.43.100901.135828[Crossref], [PubMed], [CAS], Google Scholar18https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXitFWqtr8%253D&md5=612df556e0644f9dd165bedc13fd7bf0Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicalsDenison, Michael S.; Nagy, Scott R.Annual Review of Pharmacology and Toxicology (2003), 43 (), 309-334CODEN: ARPTDI; ISSN:0362-1642. (Annual Reviews Inc.)A review. The induction of expression of genes for xenobiotic metabolizing enzymes in response to chem. insult is an adaptive response found in most organisms. In vertebrates, the AhR is one of several chem./ligand-dependent intracellular receptors that can stimulate gene transcription in response to xenobiotics. The ability of the AhR to bind and be activated by a range of structurally divergent chems. suggests that the AhR contains a rather promiscuous ligand binding site. In addn. to synthetic and environmental chems., numerous naturally occurring dietary and endogenous AhR ligands have also been identified. In this review, we describe evidence for the structural promiscuity of AhR ligand binding and discuss the current state of knowledge with regards to the activation of the AhR signaling pathway by naturally occurring exogenous and endogenous ligands.
- 19Dertinger, S. D., Silverstone, A. E., and Gasiewicz, T. A. (1998) Influence of aromatic hydrocarbon receptor-mediated events on the genotoxicity of cigarette smoke condensate. Carcinogenesis 19 (11), 2037– 2042, DOI: 10.1093/carcin/19.11.2037[Crossref], [PubMed], [CAS], Google Scholar19https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXnvVCmsrs%253D&md5=d0965b274f91b88494b72085388c39cfInfluence of aromatic hydrocarbon receptor-mediated events on the genotoxicity of cigarette smoke condensateDertinger, Stephen D.; Silverstone, Allen E.; Gasiewicz, Thomas A.Carcinogenesis (1998), 19 (11), 2037-2042CODEN: CRNGDP; ISSN:0143-3334. (Oxford University Press)The role of arom. hydrocarbon receptor (AhR)-mediated events on the genotoxicity of mainstream cigarette smoke condensate was investigated. In vitro studies with mouse hepatoma cells stably transfected with a DRE-dependent luciferase reporter indicate that cigarette smoke condensate is able to transform AhR to an active form which is capable of initiating gene transcription. Micronucleus formation in two hepatoma cell lines was used as an index of genotoxicity. Cigarette smoke condensate was obsd. to induce a higher frequency of micronuclei in Hepa1c1c7 cells relative to TAOc1BPrc1 cells, which express ∼10-fold less AhR. Furthermore, the frequency of micronuclei was potentiated when Hepa1c1c7 cells were pretreated with 2,3,7,8-tetrachlorodibenzo-p-dioxin, a high affinity ligand of AhR. These in vitro studies were followed by an in vivo expt. with Ahr+/+ and Ahr-/- mice. Animals were dosed for three consecutive days with cigarette smoke condensate (0.5-10 μg/kg/day, i.p. injection). The frequency of micronuclei in reticulocytes and total erythrocytes was detd. in peripheral blood samples collected 24 h after the last administration. While condensate was found to increase the incidence of micronucleated reticulocytes in Ahr+/+ mice, no increase was obsd. in the null allele animals. Furthermore, the frequency of micronucleated erythrocytes, a measure of basal chromosome-damaging activity, was slightly but significantly higher in Ahr+/+ relative to Ahr-/- mice. Together, these data suggest that cigarette smoke contains chems. which transform the AhR to an active transcription factor and AhR-regulated enzyme induction plays an important role in mediating the genotoxicity of this complex environmental pollutant.
- 20Ono, Y., Torii, K., Fritsche, E., Shintani, Y., Nishida, E., Nakamura, M., Shirakata, Y., Haarmann-Stemmann, T., Abel, J., Krutmann, J., and Morita, A. (2013) Role of the aryl hydrocarbon receptor in tobacco smoke extract-induced matrix metalloproteinase-1 expression. Exp. Dermatol. 22 (5), 349– 353, DOI: 10.1111/exd.12148[Crossref], [PubMed], [CAS], Google Scholar20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtVWmsrbL&md5=c3506da4a84759de6f76aada6ec21c1cRole of the aryl hydrocarbon receptor in tobacco smoke extract-induced matrix metalloproteinase-1 expressionOno, Yuko; Torii, Kan; Fritsche, Ellen; Shintani, Yoichi; Nishida, Emi; Nakamura, Motoki; Shirakata, Yuji; Haarmann-Stemmann, Thomas; Abel, Josef; Krutmann, Jean; Morita, AkimichiExperimental Dermatology (2013), 22 (5), 349-353CODEN: EXDEEY; ISSN:1600-0625. (Wiley-Blackwell)Findings from large epidemiol. studies indicate that there is a link between smoking and extrinsic skin ageing. We previously reported that matrix metaUoproteinases (MMPs) mediate connective tissue damage in skin exposed to tobacco smoke exts. Tobacco smoke contains more than 3800 constituents, including numerous water-insol. polycyclic arom. hydrocarbons (PAHs) that trigger aryl hydrocarbon receptor (AhR) signalling pathways. To analyze the mol. mechanisms involved in tobacco smoke-induced skin ageing, we exposed primary human fibroblasts and keratinocytes to tobacco smoke exts. Hexane- and water-sol. tobacco smoke exts. significantly induced MMP-1 mRNA in both human cultured fibroblasts and keratinocytes in a dose-dependent manner. To clarify the involvement of the AhR pathway, we used a stable AhR-knockdown HaCaT cell line. AhR knockdown abolished the increased transcription of the AhR-dependent genes CYP1A1/CYP1B1 and MMP-1 induced by either of the tobacco smoke exts. Furthermore, the tobacco smoke exts. induced 7-ethoxyresorufin-O-deethylase activity, which was almost completely abolished by AhR knockdown. Likewise, treating fibroblasts with AhR pathway inhibitors, i.e., the flavonoids 3-methoxy-4-nitroflavone and α-naphthoflavone, blocked the expression of CYP1B1 and MMP-1. These findings suggest that the tobacco smoke exts. induce MMP-1 expression in human fibroblasts and keratinocytes via activation of the AhR pathway. Thus, the AhR pathway may be pathogenetically involved in extrinsic skin ageing.
- 21Kitamura, M. and Kasai, A. (2007) Cigarette smoke as a trigger for the dioxin receptor-mediated signaling pathway. Cancer Lett. 252 (2), 184– 194, DOI: 10.1016/j.canlet.2006.11.015[Crossref], [PubMed], [CAS], Google Scholar21https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXlvVyitLg%253D&md5=30b74c90b55f70897d03cce6fb7e7008Cigarette smoke as a trigger for the dioxin receptor-mediated signaling pathwayKitamura, Masanori; Kasai, AyumiCancer Letters (Amsterdam, Netherlands) (2007), 252 (2), 184-194CODEN: CALEDQ; ISSN:0304-3835. (Elsevier B.V.)A review and discussion. Dioxins and dioxin-like chems. cause a wide range of pathologies including carcinogenesis, immune dysfunction, and developmental/reproductive abnormalities. Most of these toxic effects are mediated by aryl hydrocarbon receptor (AhR; also called the dioxin receptor), a ligand-activated transcription factor. Constitutive activation of AhR via genetic manipulation causes development of cancers, inflammation and immune abnormality in mice even without exposure to xenobiotic ligands. Recent investigation disclosed that cigarette smoke contains high levels of agonists for AhR and strongly activates the dioxin signaling pathway. In this review, the authors describe and discuss possible roles of AhR activation in cigarette smoke-related pathologies, esp., focusing on carcinogenesis, inflammation, atherosclerosis, immune dysfunction and teratogenesis.
- 22Meek, M. D. and Finch, G. L. (1999) Diluted mainstream cigarette smoke condensates activate estrogen receptor and aryl hydrocarbon receptor-mediated gene transcription. Environ. Res. 80 (1), 9– 17, DOI: 10.1006/enrs.1998.3872[Crossref], [PubMed], [CAS], Google Scholar22https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXltFalsg%253D%253D&md5=57766c4eda06900a532375cd24c62476Diluted mainstream cigarette smoke condensates activate estrogen receptor and aryl hydrocarbon receptor-mediated gene transcriptionMeek, Murray D.; Finch, Gregory L.Environmental Research (1999), 80 (1), 9-17CODEN: ENVRAL; ISSN:0013-9351. (Academic Press)Epidemiol. data indicate that in females cigarette smoking exerts antiestrogenic effects that manifest clin. in an increased incidence of osteoporosis, earlier menopause, increased spot bleeding, and decreased risk of endometrial cancer for female smokers. The mol. mechanism of this effect is unclear; however, decreased serum estrogen levels in female smokers have been correlated with increased concns. of the metabolite 2-hydroxyestrogen in females who smoke. Induction of estrogen metabolizing enzymes, CYP1A1 and 1A2, is one mechanism by which increased 2-hydroxyestrogen concns. may occur. It has also been suggested that the estrogen receptor (ER) may contribute to this anti-estrogenic effect by binding to antagonist(s) in cigarette smoke. Gel retardation anal. was employed to det. if dild. mainstream cigarette smoke condensates (DMCSCs) could activate the aryl hydrocarbon receptor (AhR). AhR-regulated ethoxyresorufin-O-deethylase (EROD) activity and dioxin response element (DRE)-mediated luciferase induction were assessed in Hepa1c1c7 mouse hepatoma cells. A competitive ligand binding assay was utilized to det. if DMCSCs could bind to the ER. ER-dependent luciferase activity was assessed in MCF-7 cells. In gel retardation assays, DMCSCs induced a protein-DNA complex when incubated with a radiolabeled wild-type DRE oligonucleotide. The complex was effectively competed by excess unlabeled DRE but not by excess unlabeled mutant DRE. In Hepa1c1c7 mouse hepatoma cells transiently transfected with a DRE-regulated luciferase reporter gene, pGudluc1.1, treatment with DMCSCs resulted in a 23- and 25-fold increase in luciferase activity (P<0.01) and an 8.5- and 10.5-fold (P<0.01) induction in EROD activity, resp. DMCSCs completely displaced bound tritiated E2 from the ER in a dose-dependent manner and induced ER-regulated luciferase activity significantly 6-fold (P<0.01), representing 86% of the maximal induction obsd. with E2. DMCSCs can bind to and transcriptionally activate the AhR and ER nuclear receptors and cause induction of DRE- and ER-regulated genes. Further study is required to identify the specific compd.(s) responsible for these activities. (c) 1999 Academic Press.
- 23Bandow, N., Altenburger, R., Streck, G., and Brack, W. (2009) Effect-directed analysis of contaminated sediments with partition-based dosing using green algae cell multiplication inhibition. Environ. Sci. Technol. 43 (19), 7343– 7349, DOI: 10.1021/es901351z[ACS Full Text
], [CAS], Google Scholar23https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtVWqtrjL&md5=456ebfe19bd8b786ced79a8e68249237Effect-Directed Analysis of Contaminated Sediments with Partition-Based Dosing Using Green Algae Cell Multiplication InhibitionBandow, Nicole; Altenburger, Rolf; Streck, Georg; Brack, WernerEnvironmental Science & Technology (2009), 43 (19), 7343-7349CODEN: ESTHAG; ISSN:0013-936X. (American Chemical Society)Effect-directed anal. (EDA) has been frequently and successfully used to identify key toxicants in sediment exts. However, by disregarding bioavailability this approach may lead to a biased prioritization of fractions and toxicants with respect to hazards and risks. To overcome this problem, the present EDA of sediment components from the Bilina River (Most, Czech Republic), that inhibit growth of the green algae Scenedesmus vacuolatus, was applied as a novel partition-based dosing technique to prioritize and identify major toxic fractions and compds. in comparison to conventional solvent dosing. The novel dosing technique is based on partitioning from loaded silicone rods to the aq. phase similar to partition processes that det. exposure in native sediment-water systems. The application of partition-based dosing had a big influence suggesting polar compds. such as triclosan as key toxicants while polycyclic arom. hydrocarbon (PAH) fractions did not exhibit significant effects. In contrast, conventional dosing prioritized mainly PAHs in agreement with previous studies. For both approaches individual toxicants could be confirmed quant. based on the index of confirmation quality (ICQ), which compares the effect of fractions and artificial mixts. of identified and quantified toxicants over the full range of effect levels. - 24Thomas, K. V., Hurst, M. R., Matthiessen, P., Sheahan, D., and Williams, R. J. (2001) Toxicity characterisation of organic contaminants in stormwaters from an agricultural headwater stream in south east England. Water Res. 35 (10), 2411– 2416, DOI: 10.1016/S0043-1354(00)00535-2[Crossref], [PubMed], [CAS], Google Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXksVSqs7k%253D&md5=caa9fb00eebed457e37a92feb0a81701Toxicity characterization of organic contaminants in stormwaters from an agricultural headwater stream in South East EnglandThomas, K. V.; Hurst, M. R.; Matthiessen, P.; Sheahan, D.; Williams, R. J.Water Research (2001), 35 (10), 2411-2416CODEN: WATRAG; ISSN:0043-1354. (Elsevier Science Ltd.)The transient movement of pesticides at biol. active concns. during storm events is considered to be a cause of biol. impoverishment in some headwater streams. The program of work described sought to identify compds. that are the cause of toxic effects during such events. Along with targeted pesticide anal., toxicity identification evaluation (TIE) procedures were used to identify compds. with a demonstrated toxic effect. These procedures were specifically directed towards isolating and attributing toxicity to classes of org. contaminants in samples collected from an English headwater stream during a storm event. The org. load was isolated by solid-phase extn. (SPE). Bioassay of the SPE ext. at ×100 whole water concns. confirmed that the samples contained substances toxic to Daphnia magna, although the raw samples were not toxic. Targeted pesticide anal. identified simazine and diuron as the major pesticides present and, using a toxicity unit (TU) approach, were shown to be responsible for a significant amt. of the obsd. conc. toxicity during a runoff event. However, they were not present in sufficient quantities to be totally responsible for a more toxic later event. By simplification of the SPE isolate using reverse-phase HPLC, fractions from which were tested for toxicity, the cause of conc. toxicity in the later event was isolated to 2 discrete fractions. GC-MS anal. of these fractions identified nonylphenol (NP), endosulfan sulfate and pendimethalin as present, with the majority of toxicity attributed to NP. The main advantage of the TIE approach is that it allows biol. active compds. with a demonstrated effect to be identified that may not be selected by more traditional techniques.
- 25Thomas, K. V., Hurst, M. R., Matthiessen, P., and Waldock, M. J. (2001) Characterization of estrogenic compounds in water samples collected from United Kingdom estuaries. Environ. Toxicol. Chem. 20 (10), 2165– 2170, DOI: 10.1002/etc.5620201005[Crossref], [PubMed], [CAS], Google Scholar25https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XitlSqsQ%253D%253D&md5=d96085b03c92e92d67f7092154c871d3Characterization of estrogenic compounds in water samples collected from United Kingdom estuariesThomas, Kevin V.; Hurst, Mark R.; Matthiessen, Peter; Waldock, Mike J.Environmental Toxicology and Chemistry (2001), 20 (10), 2165-2170CODEN: ETOCDK; ISSN:0730-7268. (SETAC Press)This report describes the identification of important estrogenic compds. in surface and sediment pore-water samples from the Tyne and Tees estuaries (UK) through the application of toxicity identification evaluation (TIE) procedures. The Tyne and Tees estuaries represent estuaries that have been historically impacted by industrial activities and continue to receive treated domestic sewage and industrial effluent. In 1998, Dabholm Gut on the Tees received a mixt. of treated and untreated effluent, while Howdon sewage treatment works (STW) discharged primary treated effluents. An estrogenically active water sample collected from Howdon STW on the Tyne was shown to contain 17β-estradiol, androsterone, and an unknown estrogenic compds. Most of the activity contained in a sample collected from the Dabholm Gut combined discharges on the Tees was also due to 17β-estradiol with addnl. activity from nonylphenol and (tentatively) bis(2-ethylhexyl)phthalate. The only sediment pore-water sample to demonstrate estrogenic activity was from Dabholm Gut.
- 26Oda, Y., Nakamura, S. I., Oki, I., Kato, T., and Shinagawa, H. (1985) Evaluation of the new system (umu-test) for the detection of environmental mutagens and carcinogens. Mutat. Res.-Environ. Muta. 147 (5), 219– 229, DOI: 10.1016/0165-1161(85)90062-7[Crossref], [PubMed], [CAS], Google Scholar26https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL2MXlvFWhsbc%253D&md5=29763ba11ff7d1d1aaa282785d80e3c0Evaluation of the new system (umu test) for the detection of environmental mutagens and carcinogensOda, Yoshimitsu; Nakamura, Seiichi; Oki, Iwashiro; Kato, Takesi; Shinagawa, HideoMutation Research, Environmental Mutagenesis and Related Subjects (1985), 147 (5), 219-29CODEN: MEMSE8 ISSN:.The umu operon in Escherichia coli, responsible for chem. and radiation mutagenesis, and the expression of the operon itself is inducible by these DNA-damaging agents. The principle of the umu test is based on the ability of the DNA-damaging agents, most of which are potential carcinogens, to induce the umu operon. A plasmid (pSK1002) carrying a fused gene umuC'-'lacZ was introduced into Salmonella typhimurium TA 1535. The strain TA 1535/pSK1002 enabled the levels of umu operon expression to be monitored by measuring the β-galactosidase activity in the cells produced by the fusion gene. Using this strain, a simple, inexpensive, and sensitive system, the umu test, for the screening of environmental mutagens and carcinogens was developed. Chems. with different structures and modes of action, including 31 known animal carcinogens, were examd. by the test to evaluate the system. The threshold sensitivity of the umu test was approx. equal to the Ames test for chems. genotoxic in both tests. By the umu test, using the single tester strain, many types of DNA-damaging agents were detected for which the Ames test requires several tester strains. Furthermore, the umu test provides a potential practical advantage for the screening of various environmental samples contg. amino acids and nutrients such as urine, serum, and foods.
- 27Johnson, J. D., Houchens, D. P., Kluwe, W. M., Craig, D. K., and Fisher, G. L. (1990) Effects of mainstream and environmental tobacco smoke on the immune system in animals and humans: a review. Crit. Rev. Toxicol. 20 (5), 369– 395, DOI: 10.3109/10408449009089870[Crossref], [PubMed], [CAS], Google Scholar27https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK38Xnslyrtg%253D%253D&md5=b292a78ae84782a19599ceb6ff467449Effects of mainstream and environmental tobacco smoke on the immune system in animals and humans: a reviewJohnson, Jerry D.; Houchens, David P.; Kluwe, William M.; Craig, Douglas K.; Fisher, Gerald L.Critical Reviews in Toxicology (1990), 20 (5), 369-95CODEN: CRTXB2; ISSN:0045-6446.A review with 219 refs. of the available information on the effects of mainstream and environmental tobacco smoke on the immune system in animals and humans.
- 28Andreoli, C., Gigante, D., and Nunziata, A. (2003) A review of in vitro methods to assess the biological activity of tobacco smoke with the aim of reducing the toxicity of smoke. Toxicol. In Vitro 17 (5–6), 587– 594, DOI: 10.1016/S0887-2333(03)00091-2[Crossref], [PubMed], [CAS], Google Scholar28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXos12ls7c%253D&md5=989892aaf073a4975cf4133bf4d1e3dbA review of in vitro methods to assess the biological activity of tobacco smoke with the aim of reducing the toxicity of smokeAndreoli, Cristina; Gigante, Daniela; Nunziata, AlfredoToxicology in Vitro (2003), 17 (5/6), 587-594CODEN: TIVIEQ; ISSN:0887-2333. (Elsevier)A review. In the last few years tobacco companies were developing several research strategies to reduce the risks assocd. with smoking. These strategies include, for example, the refining of alternative cigarette designs that reduce the amt. of hazardous chems. in the mainstream smoke by introducing modified filters, and/or reducing the amt. of biol. significant ingredients in tobacco-burning cigarettes. In the last few decades numerous studies were published to assess the biol. activity of tobacco smoke using in vivo and in vitro test systems. In this scenario a general scientific consensus on how to measure and characterize the risk assocd. with cigarette smoke is still lacking. Short-term in vitro assays, which are widely accepted by regulatory agencies around the world, are useful tools to evaluate both the biol. activity and the progress towards a redn. of tobacco smoke toxicity. These assays could be mainly applied to evaluate cytotoxicity and genotoxicity properties on whole cigarette smoke as well as condensates or fractions of whole smoke. Cytotoxicity induction can be measured as cellular viability and growth rates using different end-points. Otherwise, the target of genotoxicity studies is the DNA mol. For genotoxicity evaluation, the end-points and cell systems should be chosen from those that are relevant and appropriate as clin. surrogate markers. In this respect, the occurrence of early biol. effect markers, such as mutational or clastogenic events (point mutations, frameshifts, micronuclei, SCE, DNA adducts) in bacterial and mammalian cells should be studied in a tiered approach following the guidelines of regulatory agencies. The choice of criteria shall be matter of discussion.
- 29(2012) Commission Implementing Regulation (EU) No 872/2012 of 1 October 2012 adopting the list of flavouring substances provided for by Regulation (EC) No 2232/96 of the European Parliament and of the Council, Introducing it in Annex I to Regulation (EC) No 1334/2008 of the European Parliament and of the Council and repealing Commission Regulation (EC) No 1565/2000 and Commission Decision 1999/217/EC Text with EEA relevance, European Commission, Brussels; https://eur-lex.europa.eu/legal-content/EN/TXT/HTML/?uri=CELEX:32012R0872&from=EN, accessed 5/1/2018.Google ScholarThere is no corresponding record for this reference.
- 30Wang, X., Liu, S., Xia, Q., Zhao, G., Guo, J., and Xie, F. (2013) Trace analysis of alkaline flavors in cut tobacco by heart-cutting multidimensional GC-GC-MS. J. Sep. Sci. 36 (23), 3750– 3757, DOI: 10.1002/jssc.201300836[Crossref], [PubMed], [CAS], Google Scholar30https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhs1WmtL%252FN&md5=c8ced2bc0f3d15344b4b060ea5f0442bTrace analysis of alkaline flavors in cut tobacco by heart-cutting multidimensional GC-GC-MSWang, Xiaoyu; Liu, Shaofeng; Xia, Qiaoling; Zhao, Ge; Guo, Jizhao; Xie, FuweiJournal of Separation Science (2013), 36 (23), 3750-3757CODEN: JSSCCJ; ISSN:1615-9306. (Wiley-VCH Verlag GmbH & Co. KGaA)Tobacco is a complex chem. matrix. The anal. of trace alk. flavors in tobacco is very difficult because of the limited peak capacity of monodimensional GC. In the present study, a home-assembled twin-oven GC-GC-MS system, with MS detection in both dimensions, has been applied to the anal. of 20 alk. volatiles in a variety of cut-tobacco samples. By transferring nine and six heart-cuts from the first apolar column to the second polar column in two sep. runs, the potential mutual interference of adjacent isomeric targets and the complex matrix could be removed. For comparative purposes, a systematic comparison of both quantification and qualification results for the cut-tobacco sample as quality control was conducted between GC-GC-MS and GC-MS. The results showed that GC-GC-MS provided higher accuracy in peak assignment and quantification. And in GC-MS, the interferences of co-elution had caused both low matched similarity in peak assignment and false-neg./-pos. results in quantification for some targets. Advantages of the developed GC-GC-MS method in the anal. of alk. flavors are its high resolving power, reliability, and simplicity.
- 31Moldoveanu, S. C. and St. Charles, F. K. (2007) Differences in the chemical composition of the particulate phase of inhaled and exhaled cigarette mainstream smoke. Beitr. Tab. Forsch. Int. 22 (4), 290– 302, DOI: 10.2478/cttr-2013-0834
- 32Brown, D. R., Clark, B. W., Garner, L. V., and Di Giulio, R. T. (2015) Zebrafish cardiotoxicity: the effects of CYP1A inhibition and AHR2 knockdown following exposure to weak aryl hydrocarbon receptor agonists. Environ. Sci. Pollut. Res. 22 (11), 8329– 8338, DOI: 10.1007/s11356-014-3969-2[Crossref], [PubMed], [CAS], Google Scholar32https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitFKmtbvN&md5=dee558b6c795cd102a63a5ea06d6b9daZebrafish cardiotoxicity: the effects of CYP1A inhibition and AHR2 knockdown following exposure to weak aryl hydrocarbon receptor agonistsBrown, Daniel R.; Clark, Bryan W.; Garner, Lindsey V. T.; Di Giulio, Richard T.Environmental Science and Pollution Research (2015), 22 (11), 8329-8338CODEN: ESPLEC; ISSN:0944-1344. (Springer)The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates many of the toxic effects of dioxin-like compds. (DLCs) and some polycyclic arom. hydrocarbons (PAHs). Strong AHR agonists, such as certain polychlorinated biphenyls and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), cause severe cardiac teratogenesis in fish embryos. Moderately strong AHR agonists, such as benzo[a]pyrene and β-naphthoflavone, have been shown to cause similar cardiotoxic effects when coupled with a cytochrome P 450 1A (CYP1A) inhibitor, such as fluoranthene (FL). We sought to det. if weak AHR agonists, when combined with a CYP1A inhibitor (FL) or CYP1A morpholino gene knockdown, are capable of causing cardiac deformities similar to moderately strong AHR agonists (Wassenberg and Di Giulio Environ Health Perspect 112(17):1658-1664, 2004a; Wassenberg and Di Giulio Res 58(2-5):163-168, 2004b; Billiard et al. Toxicol Sci 92(2):526-536, 2006; Van Tiem and Di Giulio Toxicol Appl Pharmacol 254(3):280-287, 2011). The weak AHR agonists included the following: carbaryl, phenanthrene, 2-methylindole, 3-methylindole, indigo, and indirubin. Danio rerio (zebrafish) embryos were first exposed to weak AHR agonists at equimolar concns. The agonists were assessed for their relative potency as inducers of CYP1 enzyme activity, measured by the ethoxyresorufin-O-deethylase (EROD) assay, and cardiac deformities. Carbaryl, 2-methylindole, and 3-methylindole induced the highest CYP1A activity in zebrafish. Expts. were then conducted to det. the individual cardiotoxicity of each compd. Next, zebrafish were coexposed to each agonist (at concns. below those detd. to be cardiotoxic) and FL in combination to assess if CYP1A inhibition could induce cardiac deformities. Carbaryl, 2-methylindole, 3-methylindole, and phenanthrene significantly increased pericardial edema relative to controls when combined with FL. To further evaluate the interaction of the weak AHR agonists and CYP1A inhibition, a morpholino was used to knockdown CYP1A expression, and embryos were then exposed to each agonist individually. In embryos exposed to 2-methylindole, CYP1A knockdown caused a similar level of pericardial edema to that caused by exposure to 2-methylindole and FL. The results showed a complex pattern of cardiotoxic response to weak agonist inhibitor exposure and morpholino-knockdown. However, CYP1A knockdown in phenanthrene and 3-methylindole only moderately increased pericardial edema relative to coexposure to FL. AHR2 expression was also knocked down using a morpholino to det. its role in mediating the obsd. cardiac teratogenesis. Knockdown of AHR2 did not rescue the pericardial edema as previously obsd. with strong AHR agonists. While some of the cardiotoxicity obsd. may be attributed to the combination of weak AHR agonism and CYP1A inhibition, other weak AHR agonists appear to be causing cardiotoxicity through an AHR2-independent mechanism. The data show that CYP1A is protective of the cardiac toxicity assocd. with weak AHR agonists and that knockdown can generate pericardial edema, but these findings are also suggestive of differing mechanisms of cardiac toxicity among known AHR agonists.
- 33Sovadinová, I., Bláha, L., Janošek, J., Hilscherová, K., Giesy, J. P., Jones, P. D., and Holoubek, I. (2006) Cytotoxicity and aryl hydrocarbon receptor-mediated activity of N-heterocyclic polycyclic aromatic hydrocarbons: Structure-activity relationships. Environ. Toxicol. Chem. 25 (5), 1291– 1297, DOI: 10.1897/05-388R.1[Crossref], [PubMed], [CAS], Google Scholar33https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XktlGjs7k%253D&md5=7e513326bad8e7eea128157c1b8fc503Cytotoxicity and aryl hydrocarbon receptor-mediated activity of N-heterocyclic polycyclic aromatic hydrocarbons: structure-activity relationshipsSovadinova, Iva; Blaha, Ludek; Janosek, Jaroslav; Hilscherova, Klara; Giesy, John P.; Jones, Paul D.; Holoubek, IvanEnvironmental Toxicology and Chemistry (2006), 25 (5), 1291-1297CODEN: ETOCDK; ISSN:0730-7268. (SETAC Press)Toxic effects of many persistent org. pollutants (e.g., polychlorinated biphenyls or polychlorinated dibenzo-p-dioxins and furans) are mediated via the aryl hydrocarbon receptor (AhR). Although polycyclic arom. hydrocarbons (PAHs) and their derivs. also activate AhR, their toxic effects remain to be fully elucidated. In the present study, the authors used the in vitro H4IIE-luc transactivation cell assay to investigate cytotoxicity and potencies to activate AhR by 29 individual PAHs and their N-heterocyclic derivs. (aza-PAHs). The aza-PAHs were found to be significantly more cytotoxic and more potent inducers of AhR than their unsubstituted analogs. Several aza-PAHs, such as dibenz[a,h]acridine or dibenz[a,i]acridine, activated AhR within picomolar concns., comparable to the effects of ref. 2,3,7,8-tetrachlorodibenzo-p-dioxin. Ellipsoidal vol., molar refractivity, and mol. size were the most important descriptors derived from the modeling of quant. structure-activity relationships for potencies to activate AhR. Comparable relative toxic potencies (induction equivalency factors) for individual aza-PAHs are derived, and their use for evaluation of complex contaminated samples is discussed.
- 34Hubbard, T. D., Murray, I. A., Bisson, W. H., Lahoti, T. S., Gowda, K., Amin, S. G., Patterson, A. D., and Perdew, G. H. (2015) Adaptation of the human aryl hydrocarbon receptor to sense microbiota-derived indoles. Sci. Rep. 5, 12689, DOI: 10.1038/srep12689[Crossref], [PubMed], [CAS], Google Scholar34https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsVKiurvL&md5=3983f2dfc263478b56331e93bd0e8d90Adaptation of the human aryl hydrocarbon receptor to sense microbiota-derived indolesHubbard, Troy D.; Murray, Iain A.; Bisson, William H.; Lahoti, Tejas S.; Gowda, Krishne; Amin, Shantu G.; Patterson, Andrew D.; Perdew, Gary H.Scientific Reports (2015), 5 (), 12689CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)Ligand activation of the aryl hydrocarbon (AHR) has profound effects upon the immunol. status of the gastrointestinal tract, establishing and maintaining signaling networks, which facilitate host-microbe homeostasis at the mucosal interface. However, the identity of the ligand(s) responsible for such AHR-mediated activation within the gut remains to be firmly established. Here, we combine in vitro ligand binding, quant. gene expression, protein-DNA interaction and ligand structure activity analyses together with in silico modeling of the AHR ligand binding domain to identify indole, a microbial tryptophan metabolite, as a human-AHR selective agonist. Human AHR, acting as a host indole receptor may exhibit a unique bimol. (2:1) binding stoichiometry not obsd. with typical AHR ligands. Such bimol. indole-mediated activation of the human AHR within the gastrointestinal tract may provide a foundation for inter-kingdom signaling between the enteric microflora and the immune system to promote commensalism within the gut.
- 35Stepankova, M., Bartonkova, I., Jiskrova, E., Vrzal, R., Mani, S., Kortagere, S., and Dvorak, Z. (2018) Methylindoles and methoxyindoles are agonists and antagonists of human aryl hydrocarbon receptor. Mol. Pharmacol. 93, 631– 644, DOI: 10.1124/mol.118.112151[Crossref], [PubMed], [CAS], Google Scholar35https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhslOnu7rK&md5=053972ffe1b5cb356823c2a572b5f4f0Methylindoles and methoxyindoles are agonists and antagonists of human aryl hydrocarbon receptorStepankova, Martina; Bartonkova, Iveta; Jiskrova, Eva; Vrzal, Radim; Mani, Sridhar; Kortagere, Sandhya; Dvorak, ZdenekMolecular Pharmacology (2018), 93 (6), 631-644CODEN: MOPMA3; ISSN:1521-0111. (American Society for Pharmacology and Experimental Therapeutics)Novel methylindoles were identified as endobiotic and xenobi- otic ligands of the human aryl hydrocarbon receptor (AhR). We examd. the effects of 22 methylated and methoxylated indoles on the transcriptional activity of AhRs. Employing reporter gene assays in AZ-AHR transgenic cells, we detd. full agonist, partial agonist, or antagonist activities of tested compds., having substantially variable EC50, IC50, and relative efficacies. The most effective agonists (EMAX relative to 5 nM dioxin) of the AhR were 4-Me-indole (134%), 6-Me-indole (91%), and 7-MeO- indole (80%), resp. The most effective antagonists of the AhR included 3-Me-indole (IC50; 19 μM), 2,3-diMe-indole (IC50; 11 μM), and 2,3,7-triMe-indole (IC50; 12 μM). Reverse transcrip- tion polymerase chain reaction analyses of CYP1A1 mRNA in LS180 cells confirmed the data from gene reporter assays. The compd. leads, 4-Me-indole and 7-MeO-indole, induced sub- stantial nuclear translocation of the AhR and enriched binding of the AhR to the CYP1A1 promoter, as obsd. using fluores- cent immunohistochem. and chromatin immunopptn. assays, resp. Mol. modeling and docking studies suggest the agonists and antagonists likely share the same binding pocket but have unique binding modes that code for their affinity. Binding pocket anal. further revealed that 4-methylindole and 7-methoxyindole can simultaneously bind to the pocket and produce synergistic interactions. Together, these data show a dependence on subtle and specific chem. indole structures as AhR modulators and furthermore under- score the importance of complete evaluation of indole com- pounds as nuclear receptor ligands.
- 36(2018) Phthalates, U.S. Food and Drug Administration, Silver Spring, MD. https://www.fda.gov/Cosmetics/ProductsIngredients/Ingredients/ucm128250.htm (accessed June 27, 2019).Google ScholarThere is no corresponding record for this reference.
- 37Liu, Q., Chen, D., Wu, J., Yin, G., Lin, Q., Zhang, M., and Hu, H. (2018) Determination of phthalate esters in soil using a quick, easy, cheap, effective, rugged, and safe method followed by GC-MS. J. Sep. Sci. 41 (8), 1812– 1820, DOI: 10.1002/jssc.201701126[Crossref], [PubMed], [CAS], Google Scholar37https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisFektbo%253D&md5=d4c4042ab50727b0a7ff16663aaafe9aDetermination of phthalate esters in soil using a quick, easy, cheap, effective, rugged, and safe method followed by GC-MSLiu, Qianjun; Chen, Di; Wu, Jiyuan; Yin, Guangcai; Lin, Qintie; Zhang, Min; Hu, HuawenJournal of Separation Science (2018), 41 (8), 1812-1820CODEN: JSSCCJ; ISSN:1615-9314. (Wiley-VCH Verlag GmbH & Co. KGaA)A quick, easy, cheap, effective, rugged, and safe procedure was designed to ext. pesticide residues from fruits and vegetables with a high percentage of water. It has not been used extensively for the extn. of phthalate esters from sediments, soils, and sludges. In this work, this procedure was combined with gas chromatog. with mass spectrometry to det. 16 selected phthalate esters in soil. The extn. efficiency of the samples was improved by ultrasonic extn. and dissoln. of the soil samples in ultra-pure water, which promoted the dispersion of the samples. Furthermore, we have simplified the extn. step and reduced the risk of org. solvent contamination by minimizing the use of org. solvents. Different extn. solvents and clean-up adsorbents were compared to optimize the procedure. Dichloromethane/n-hexane (1:1, vol./vol.) and n-hexane/acetone (1:1, vol./vol.) were selected as the extractants from the six extn. solvents tested. C18/primary secondary amine (1:1, m/m) was selected as the sorbent from the five clean-up adsorbents tested. The recoveries from the spiked soils ranged from 70.00 to 117.90% with relative std. deviation values of 0.67-4.62%. The proposed approach was satisfactorily applied for the detn. of phthalate esters in 12 contaminated soil samples.
- 38Zhu, F., Mao, C., and Du, D. (2017) Time-resolved immunoassay based on magnetic particles for the detection of diethyl phthalate in environmental water samples. Sci. Total Environ. 601, 723– 731, DOI: 10.1016/j.scitotenv.2017.05.111[Crossref], [PubMed], [CAS], Google Scholar38https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXpt12lt7o%253D&md5=174d2024699aefb1de48f956dfdb2902Time-resolved immunoassay based on magnetic particles for the detection of diethyl phthalate in environmental water samplesZhu, Fang; Mao, Chaoming; Du, DaolinScience of the Total Environment (2017), 601-602 (), 723-731CODEN: STENDL; ISSN:0048-9697. (Elsevier B.V.)Di-Et phthalate (DEP) is an extensively used phthalic acid diester (PAEs) with estrogenic activity and the potential for carcinogenic and teratogenic effects. To monitor trace DEP in environmental waters, a sensitive direct competitive time-resolved fluoroimmunoassay based on magnetic particles (MPs) as solid support was established. For the assay system, the anti-DEP antibody was oriented on the surface of the MPs using goat anti-rabbit antibody as linkers, and DEP-OVA was labeled using Eu3 +. Several physicochem. factors that potentially influence the assay performance of the proposed method were studied in detail, including concn. of MPs, diln. of DEP-OVA-Eu3 + and incubation time. Under the optimized conditions, the method showed: (i) low limit of detection (LOD) of 5.92 ng/L; (ii) satisfactory accuracy (recoveries, 91.97-134.54%) with good reproducibility (inter-CV, 4.17-9.17%; intra-CV, 7.41-14.72%). All of which indicated that the newly established method had much higher efficiency and great potential for use in environmental water anal. for DEP. In addn., the proposed immunoassay was applied for study of DEP in aquatic environments at Zhenjiang City. The authors' results showed that DEP was detected at the concn. of 2.98-65.18 ng/mL in river samples and 46.95-306.19 ng/mL in wastewater treatment plants (WWTPs), which showed rather high concns. compared with reported data. The authors' study provides background data important for risk assessment and contamination control of DEP in the aquatic environment of this area.
- 39Kadi, M. W., Ali, N., and Albar, H. M. S. A. (2018) Phthalates and polycyclic aromatic hydrocarbons (PAHs) in the indoor settled carpet dust of mosques, health risk assessment for public. Sci. Total Environ. 627, 134– 140, DOI: 10.1016/j.scitotenv.2018.01.146[Crossref], [PubMed], [CAS], Google Scholar39https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitFygu7s%253D&md5=def428f8fffa31ade249fd284d6844f0Phthalates and polycyclic aromatic hydrocarbons (PAHs) in the indoor settled carpet dust of mosques, health risk assessment for publicKadi, Mohammad W.; Ali, Nadeem; Albar, Hussain Mohammed Salem AliScience of the Total Environment (2018), 627 (), 134-140CODEN: STENDL; ISSN:0048-9697. (Elsevier B.V.)A no. of studies have reported the occurrence of phthalates and polycyclic arom. hydrocarbons (PAHs) in indoor settled dust from different occupational and residential settings around the world but limited studies are available from public and religious places. In recent decades Kingdom of Saudi Arabia (KSA) has experienced tremendous industrial growth esp. in the petroleum industries, and as result environmental issues related with such industries have also increased but scientific data is still scarce to understand the impact on public health. Therefore, the main objective of this study was to report the phthalates and PAHs profile in the settled dust collected from various mosques of Jeddah, an important part of people living in the region, and to evaluate the health risk assocd. with these chems. via dust ingestion, inhalation and dermal contact for the general public who attend mosques for prayers. Phenanthrene (500-3000ng/g), pyrene (40-1220ng/g), and chrysene (95-4590ng/g) were the major PAHs and .sum.12PAHs concns. ranged from 2550 to 9150ng/g. Whereas, DEHP (<LOQ-292900 ng/g) and BzBP (<LOQ-292900 ng/g) were the major phthalates in the mosque dust. Health risk assessment for the public was calcd. by incremental lifetime cancer risk (ILCR), and daily exposure to via dust ingestion, inhalation, and dermal contact for both PAHs and phthalates. At the same time, benzo[a]pyrene equiv. carcinogenic power (BaPE) (median 145ng/g) was calcd. for PAHs. The ILCR for PAHs was in line with the ref. values of USEPA. At the same time, exposure via dust ingestion on daily basis reached up to 82ng/kg bw/day for DEHP for young children. The study showed general public is exposed to these chems. in the studied area and major exposure routes are dermal and ingestion.
- 40(2012). Endocrine Disruptor Screening Program (EDSP) Universe of Chemicals, U.S. Environmental Protection Agency, Washington, DC.Google ScholarThere is no corresponding record for this reference.
- 41Mankidy, R., Wiseman, S., Ma, H., and Giesy, J. P. (2013) Biological impact of phthalates. Toxicol. Lett. 217 (1), 50– 58, DOI: 10.1016/j.toxlet.2012.11.025[Crossref], [PubMed], [CAS], Google Scholar41https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXnvFCmsg%253D%253D&md5=3f2b6ee66eec606999c90c703cbebda6Biological impact of phthalatesMankidy, Rishikesh; Wiseman, Steve; Ma, Hong; Giesy, John P.Toxicology Letters (2013), 217 (1), 50-58CODEN: TOLED5; ISSN:0378-4274. (Elsevier Ireland Ltd.)Esters of phthalic acid are chem. agents used to improve the plasticity of industrial polymers. Their ubiquitous use in multiple com. products results in extensive exposure to humans and the environment. This study investigated cytotoxicity, endocrine disruption, effects mediated via AhR, lipid peroxidn. and effects on expression of enzymes of xenobiotic metab. caused by di-(2-ethy hexyl) phthalate (DEHP), di-Et phthalate (DEP), di-Bu phthalate (DBP) and benzyl Bu phthalate (BBP) in developing fish embryos. Oxidative stress was identified as the crit. mechanism of toxicity (CMTA) in the case of DEHP and DEP, while the efficient removal of DBP and BBP by phase 1 enzymes resulted in lesser toxicity. DEHP and DEP did not mimic estradiol (E2) in transactivation studies, but at concns. of 10 mg/L synthesis of sex steroid hormones was affected. Exposure to 10 mg BBP/L resulted in weak transactivation of the estrogen receptor (ER). All phthalates exhibited weak potency as agonists of the aryl hydrocarbon receptor (AhR). The order of potency of the 4 phthalates studied was; DEHP > DEP > BBP > > DBP. The study highlights the need for simultaneous assessment of: multiple cellular targets affected by phthalates and phthalate mixts. to account for additive effects when multiple phthalates modulate the same pathway. Such cumulative assessment of multiple biol. parameters is more realistic, and offers the possibility of more accurately identifying the CMTA.
- 42Harris, C. A., Henttu, P., Parker, M. G., and Sumpter, J. P. (1997) The estrogenic activity of phthalate esters in vitro. Environ. Health Perspect. 105 (8), 802, DOI: 10.1289/ehp.97105802[Crossref], [CAS], Google Scholar42https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXnt1GjurY%253D&md5=735feeb0cad72ea9168208dc1fe8c28eThe estrogenic activity of phthalate esters in vitroHarris, Catherine A.; Henttu, Pirkko; Parker, Malcolm G.; Sumpter, John P.Environmental Health Perspectives (1997), 105 (8), 802-811CODEN: EVHPAZ; ISSN:0091-6765. (National Institute of Environmental Health Sciences)A large no. of phthalate esters were screened for estrogenic activity using a recombinant yeast screen. A selection of these was also tested for mitogenic effect on estrogen-responsive human breast cancer cells. A small no. of the com. available phthalates tested showed extremely weak estrogenic activity. The relative potencies of these descended in the order Bu benzyl phthalate (BBP)>dibutyl phthalate (DBP)>diisobutyl phthalate (DIBP)>diethyl phthalate (DEP)>diisononyl phthalate (DINP). Potencies ranged from approx. 1 × 106 to 5 × 107 times less than 17β-estradiol. The phthalates that were estrogenic in the yeast screen were also mitogenic on the human breast cancer cells. Di(2-ethylhexyl) phthalate (DEHP) showed no estrogenic activity in these in vitro assays. A no. of metabolites were tested, including mono-Bu phthalate, mono-benzyl phthalate, mono-ethylhexyl phthalate, mono-n-octyl phthalate; all were found to be inactive. One of the phthalates, ditridecyl phthalate (DTDP), produced inconsistent results; one sample was weakly estrogenic, whereas another, obtained from a different source, was inactive. Anal. by gel chromatog.-mass spectrometry showed that the prepn. exhibiting estrogenic activity contained 0.5% of the ortho-isomer of bisphenol A. It is likely that the presence of this antioxidant in the phthalate std. was responsible for the generation of a dose-response curve-which was not obsd. with an alternative sample that had not been supplemented with o,p'-bisphenol A-in the yeast screen; hence, DTDP is probably not weakly estrogenic. The activities of simple mixts. of BBP, DBP, and 17β-estradiol were assessed in the yeast screen. No synergism was obsd., although the activities of the mixts. were approx. additive. In summary, a small no. of phthalates are weakly estrogenic in vitro. No data has yet been published on whether these are also estrogenic in vivo; this will require tests using different classes of vertebrates and different routes of exposure.
- 43Kumar, N., Sharan, S., Srivastava, S., and Roy, P. (2014) Assessment of estrogenic potential of diethyl phthalate in female reproductive system involving both genomic and non-genomic actions. Reprod. Toxicol. 49, 12– 26, DOI: 10.1016/j.reprotox.2014.06.008[Crossref], [PubMed], [CAS], Google Scholar43https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXht1Ojs7vO&md5=e5097492c564bfa86469c0f5fb742371Assessment of estrogenic potential of diethyl phthalate in female reproductive system involving both genomic and non-genomic actionsKumar, Narender; Sharan, Shruti; Srivastava, Swati; Roy, ParthaReproductive Toxicology (2014), 49 (), 12-26CODEN: REPTED; ISSN:0890-6238. (Elsevier Inc.)Phthalates are the diverse group of compds. abundantly present in environment. The present study shows the estrogenic potential of di-Et phthalate (DEP). The data showed that DEP increased the transactivation of ER in CHO and MCF-7 cells suggesting its interaction with ER. In vivo parameters like increased uterine epithelial cell height and up regulation of various steroidogenic genes were also obsd. in adult female rats. Our uterotrophic assay data from immature female rats suggested that DEP treatment resulted in augmentation of uterine wt. as well as luminal epithelial cell heights in both vaginal and uterine tissues. Further, DEP was able to upregulate pS2 gene expression with simultaneous activation of MAPK pathway as demonstrated by increased p-ERK/ERK ratio. Taken together, the present data suggests that DEP acts as an estrogenic compd. and based on these data further detailed studies would reveal its mode of action at cellular levels.
- 44Akalin, M. K. and Karagoz, S. (2011) Pyrolysis of tobacco residue: part 1. Thermal. BioResources 6 (2), 1520– 1531Google ScholarThere is no corresponding record for this reference.
- 45Yin, C., Xu, Z., Shu, J., Wang, H., Li, Y., Sun, W., Zhou, Z., Chen, M., and Zhong, F. (2014) Study on the effect of potassium lactate additive on the combustion behavior and mainstream smoke of cigarettes. J. Therm. Anal. Calorim. 115 (2), 1733– 1751, DOI: 10.1007/s10973-013-3478-4[Crossref], [CAS], Google Scholar45https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhslWisrzO&md5=4c54211783d3f6d2f4c3165c1e264909Study on the effect of potassium lactate additive on the combustion behavior and mainstream smoke of cigarettesYin, Chunyan; Xu, Zhiqiang; Shu, Junsheng; Wang, Hua; Li, Yue; Sun, Weifeng; Zhou, Zhilei; Chen, Maoshen; Zhong, FangJournal of Thermal Analysis and Calorimetry (2014), 115 (2), 1733-1751CODEN: JTACF7; ISSN:1388-6150. (Springer)The influence of potassium lactate (PL) on the combustion behavior and semi-volatile compds. of tobacco during smoking is investigated in this study. The addn. of PL showed no effect on the content of total particulate matter, nicotine-free dry particulate matter, puff no., and nicotine. Meanwhile, a 22.5 % increase in moisture content and 3 % decrease in CO content of mainstream smoke were obsd. when the added amt. of PL was up to 2 %. The differential thermogravimetric curves indicated that PL decreased the max. combustion rate and influenced the thermal degrdn. stage of tobacco by shifting the peak point of temp. to a higher value. The gas evolution profiles obtained from Fourier transform IR spectroscopy during combustion showed that PL could lower the CO and CO2 yield, but did not affect the generation of CH4 and carbonyl compds. A great variation in semi-volatile components of the mainstream smoke was also obsd. from the tobacco contg. PL compared with the control. The comprehensive two-dimensional gas chromatog. coupled to time-of-flight mass spectrometry anal. showed that PL increased the yield of alcs., lactons, misc. oxygenated compds. and amides, but decreased that of aldehydes, acids, pyrroles and pyrazines. A small added amt. (0.2 %) of PL reduced the content of total semi-volatile substances, ketones, esters, phenols, hydrocarbons, pyridines, tobacco alkaloids, and nitrogenous compd. However, the contents of these substances were not affected when the added amt. was >0.2 %. PL bound the ash during combustion, thereby leading to the change of combustion behavior and certain smoke components.
- 46Stabbert, R., Dempsey, R., Diekmann, J., Euchenhofer, C., Hagemeister, T., Haussmann, H. J., Knorr, A., Mueller, B. P., Pospisil, P., Reininghaus, W., Roemer, E. (2017) Studies on the contributions of smoke constituents, individually and in mixtures, in a range of in vitro bioactivity assays. Toxicol. In Vitro 42, 222– 246, DOI: 10.1016/j.tiv.2017.04.003[Crossref], [PubMed], [CAS], Google Scholar46https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXnsVart74%253D&md5=65be46f8eaa06e604a0fcd2c3c4a9083Studies on the contributions of smoke constituents, individually and in mixtures, in a range of in vitro bioactivity assaysStabbert, Regina; Dempsey, Ruth; Diekmann, Joerg; Euchenhofer, Christian; Hagemeister, Timo; Haussmann, Hans-Juergen; Knorr, Arno; Mueller, Boris P.; Pospisil, Pavel; Reininghaus, Wolf; Roemer, Ewald; Tewes, Franz J.; Veltel, Detlef J.Toxicology In Vitro (2017), 42 (), 222-246CODEN: TIVIEQ; ISSN:0887-2333. (Elsevier Ltd.)Tobacco smoke is a complex mixt. with over 8700 identified constituents. Smoking causes many diseases including lung cancer, cardiovascular disease, and chronic obstructive pulmonary disease. However, the mechanisms of how cigarette smoke impacts disease initiation or progression are not well understood and individual smoke constituents causing these effects are not generally agreed upon. The studies reported here were part of a series of investigations into the contributions of selected smoke constituents to the biol. activity of cigarette smoke. In vitro cytotoxicity measured by the neutral red uptake (NRU) assay and in vitro mutagenicity detd. in the Ames bacterial mutagenicity assay (BMA) were selected because these assays are known to produce reproducible, quant. for cigarette smoke under standardized exposure conditions. To det. the contribution of individual cigarette smoke constituents, a fingerprinting method was developed to semi-quantify the mainstream smoke yields. For cytotoxicity, 90% of gas vapor phase (GVP) cytotoxicity of the Kentucky Ref. cigarette 1R4F was explained by 3 aldehydes and 40% of the 1R4F particulate phase cytotoxicity by 10 smoke constituents, e.g., hydroquinone. In the microsuspension version of the BMA, 4 aldehydes accounted for approx. 70% of the GVP mutagenicity. Finally, the benefits of performing such studies along with the difficulties in interpretation in the context of smoking are discussed.
- 47Wright, S. L., Rowe, D., Reid, M. J., Thomas, K. V., and Galloway, T. S. (2015) Bioaccumulation and biological effects of cigarette litter in marine worms. Sci. Rep. 5, 14119, DOI: 10.1038/srep14119[Crossref], [PubMed], [CAS], Google Scholar47https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsFeis7zP&md5=94ccd4df76ee309bb079604728c88c66Bioaccumulation and biological effects of cigarette litter in marine wormsWright, Stephanie L.; Rowe, Darren; Reid, Malcolm J.; Thomas, Kevin V.; Galloway, Tamara S.Scientific Reports (2015), 5 (), 14119CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)Marine debris is a global environmental issue. Smoked cigarette filters are the predominant coastal litter item; 4.5 trillion are littered annually, presenting a source of bioplastic microfibres (cellulose acetate) and harmful toxicants to marine environments. Despite the human health risks assocd. with smoking, little is known of the hazards cigarette filters present to marine life. Here we studied the impacts of smoked cigarette filter toxicants and microfibres on the polychaete worm Hediste diversicolor (ragworm), a widespread inhabitant of coastal sediments. Ragworms exposed to smoked cigarette filter toxicants in seawater at concns. 60 fold lower than those reported for urban run-off exhibited significantly longer burrowing times, >30% wt. loss, and >2-fold increase in DNA damage compared to ragworms maintained in control conditions. In contrast, ragworms exposed to smoked cigarette filter microfibres in marine sediment showed no significant effects. Bioconcn. factors for nicotine were 500 fold higher from seawater than from sediment. Our results illustrate the vulnerability of organisms in the water column to smoking debris and assocd. toxicants, and highlight the risks posed by smoked cigarette filter debris to aquatic life.
- 48Benowitz, N. L., Hukkanen, J., and Jacob, P. (2009). Nicotine chemistry, metabolism, kinetics and biomarkers. In Nicotine psychopharmacology, pp 29– 60, Springer, Berlin, Heidelberg.
Supporting Information
ARTICLE SECTIONSThe Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.chemrestox.9b00201.
Mass spectra of unknown compounds found in AhR-responsive samples; instrument conditions of GC × GC/TOF-MS for the chemical analyses; and chemical analysis information on six unknown compounds found in AhR-responsive samples (PDF)
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