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  1. Artikel ; Online: The skin sensitization adverse outcome pathway: exploring the role of mechanistic understanding for higher tier risk assessment.

    Aleksic, Maja / Rajagopal, Ramya / de-Ávila, Renato / Spriggs, Sandrine / Gilmour, Nicola

    Critical reviews in toxicology

    2024  Band 54, Heft 2, Seite(n) 69–91

    Abstract: For over a decade, the skin sensitization Adverse Outcome Pathway (AOP) has served as a useful framework for development of ... ...

    Abstract For over a decade, the skin sensitization Adverse Outcome Pathway (AOP) has served as a useful framework for development of novel
    Mesh-Begriff(e) Humans ; Animals ; Adverse Outcome Pathways ; Dermatitis, Allergic Contact ; Reproducibility of Results ; Skin ; Risk Assessment ; Animal Testing Alternatives
    Sprache Englisch
    Erscheinungsdatum 2024-02-22
    Erscheinungsland England
    Dokumenttyp Journal Article ; Review
    ZDB-ID 1097071-x
    ISSN 1547-6898 ; 1040-8444
    ISSN (online) 1547-6898
    ISSN 1040-8444
    DOI 10.1080/10408444.2024.2308816
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  2. Artikel ; Online: ADME characterization and PBK model development of 3 highly protein-bound UV filters through topical application.

    Li, Hequn / Bunglawala, Fazila / Hewitt, Nicola J / Pendlington, Ruth / Cubberley, Richard / Nicol, Beate / Spriggs, Sandrine / Baltazar, Maria / Cable, Sophie / Dent, Matthew

    Toxicological sciences : an official journal of the Society of Toxicology

    2023  Band 196, Heft 1, Seite(n) 1–15

    Abstract: Estimating human exposure in the safety assessment of chemicals is crucial. Physiologically based kinetic (PBK) models which combine information on exposure, physiology, and chemical properties, describing the absorption, distribution, metabolism, and ... ...

    Abstract Estimating human exposure in the safety assessment of chemicals is crucial. Physiologically based kinetic (PBK) models which combine information on exposure, physiology, and chemical properties, describing the absorption, distribution, metabolism, and excretion (ADME) processes of a chemical, can be used to calculate internal exposure metrics such as maximum concentration and area under the concentration-time curve in plasma or tissues of a test chemical in next-generation risk assessment. This article demonstrates the development of PBK models for 3 UV filters, specifically octyl methoxycinnamate, octocrylene, and 4-methylbenzylidene camphor. The models were parameterized entirely based on data obtained from in vitro and/or in silico methods in a bottom-up modeling approach and then validated based on human dermal pharmacokinetic (PK) data. The 3 UV filters are "difficult to test" in in vitro test systems due to high lipophilicity, high binding affinity for proteins, and nonspecific binding, for example, toward plastic. This research work presents critical considerations in ADME data generation, interpretation, and parameterization to assure valid PBK model development to increase confidence in using PBK modeling to help make safety decisions in the absence of human PK data. The developed PBK models of the 3 chemicals successfully simulated the plasma concentration profiles of clinical PK data following dermal application, indicating the reliability of the ADME data generated and the parameters determined. The study also provides insights and lessons learned for characterizing ADME and developing PBK models for highly lipophilic and protein-bound chemicals in the future.
    Mesh-Begriff(e) Humans ; Models, Biological ; Reproducibility of Results ; Kinetics ; Risk Assessment ; In Vitro Techniques
    Sprache Englisch
    Erscheinungsdatum 2023-08-15
    Erscheinungsland United States
    Dokumenttyp Journal Article
    ZDB-ID 1420885-4
    ISSN 1096-0929 ; 1096-6080
    ISSN (online) 1096-0929
    ISSN 1096-6080
    DOI 10.1093/toxsci/kfad081
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  3. Artikel ; Online: A study of inter-individual variability in the Phase II metabolism of xenobiotics in human skin.

    Spriggs, Sandrine / Cubberley, Richard / Loadman, Paul / Sheffield, David / Wierzbicki, Antonia

    Toxicology letters

    2018  Band 292, Seite(n) 63–72

    Abstract: Understanding skin metabolism is key to improve in vitro to in vivo extrapolations used to inform risk assessments of topically applied products. However, published literature is scarce and usually covers a limited and non-representative number of donors. ...

    Abstract Understanding skin metabolism is key to improve in vitro to in vivo extrapolations used to inform risk assessments of topically applied products. However, published literature is scarce and usually covers a limited and non-representative number of donors. We developed a protocol to handle and store ex vivo skin samples post-surgery and prepare skin S9 fractions to measure the metabolic activity of Phase II enzymes. Preincubation of an excess of cofactors at 37 °C for fifteen minutes in the S9 before introduction of the testing probe, greatly increased the stability of the enzymes. Using this standardised assay, the rates of sulphation (SULT) and glucuronidation (UGT) of 7-hydroxycoumarin, methylation (COMT) of dopamine and N-acetylation (NAT) of procainamide were measured in the ng/mg protein/h (converted to ng/cm
    Mesh-Begriff(e) Acetylation ; Adolescent ; Adult ; Age Factors ; Aged ; Aged, 80 and over ; Biological Variation, Population ; Cryopreservation ; Dinitrochlorobenzene/metabolism ; Dopamine/metabolism ; Enzyme Stability ; Female ; Glucuronides/metabolism ; Glutathione/analogs & derivatives ; Glutathione/metabolism ; Humans ; Kinetics ; Linear Models ; Male ; Metabolic Detoxication, Phase II ; Methylation ; Middle Aged ; Procainamide/metabolism ; Sex Factors ; Skin/enzymology ; Sulfates/metabolism ; Umbelliferones/metabolism ; Young Adult
    Chemische Substanzen Glucuronides ; Sulfates ; Umbelliferones ; 7-hydroxycoumarin (60Z60NTL4G) ; Glutathione (GAN16C9B8O) ; Dinitrochlorobenzene (GE3IBT7BMN) ; Procainamide (L39WTC366D) ; Dopamine (VTD58H1Z2X)
    Sprache Englisch
    Erscheinungsdatum 2018-08
    Erscheinungsland Netherlands
    Dokumenttyp Comparative Study ; Journal Article
    ZDB-ID 433788-8
    ISSN 1879-3169 ; 0378-4274
    ISSN (online) 1879-3169
    ISSN 0378-4274
    DOI 10.1016/j.toxlet.2018.04.011
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  4. Artikel ; Online: Development of a human liver microphysiological coculture system for higher throughput chemical safety assessment.

    Ip, Blanche C / Madnick, Samantha J / Zheng, Sophia / van Tongeren, Tessa C A / Hall, Susan J / Li, Hui / Martin, Suzanne / Spriggs, Sandrine / Carmichael, Paul / Chen, Wei / Ames, David / Breitweiser, Lori A / Pence, Heather E / Bowling, Andrew J / Johnson, Kamin J / Cubberley, Richard / Morgan, Jeffrey R / Boekelheide, Kim

    Toxicological sciences : an official journal of the Society of Toxicology

    2024  Band 199, Heft 2, Seite(n) 227–245

    Abstract: Chemicals in the systemic circulation can undergo hepatic xenobiotic metabolism, generate metabolites, and exhibit altered toxicity compared with their parent compounds. This article describes a 2-chamber liver-organ coculture model in a higher- ... ...

    Abstract Chemicals in the systemic circulation can undergo hepatic xenobiotic metabolism, generate metabolites, and exhibit altered toxicity compared with their parent compounds. This article describes a 2-chamber liver-organ coculture model in a higher-throughput 96-well format for the determination of toxicity on target tissues in the presence of physiologically relevant human liver metabolism. This 2-chamber system is a hydrogel formed within each well consisting of a central well (target tissue) and an outer ring-shaped trough (human liver tissue). The target tissue chamber can be configured to accommodate a three-dimensional (3D) spheroid-shaped microtissue, or a 2-dimensional (2D) cell monolayer. Culture medium and compounds freely diffuse between the 2 chambers. Human-differentiated HepaRG liver cells are used to form the 3D human liver microtissues, which displayed robust protein expression of liver biomarkers (albumin, asialoglycoprotein receptor, Phase I cytochrome P450 [CYP3A4] enzyme, multidrug resistance-associated protein 2 transporter, and glycogen), and exhibited Phase I/II enzyme activities over the course of 17 days. Histological and ultrastructural analyses confirmed that the HepaRG microtissues presented a differentiated hepatocyte phenotype, including abundant mitochondria, endoplasmic reticulum, and bile canaliculi. Liver microtissue zonation characteristics could be easily modulated by maturation in different media supplements. Furthermore, our proof-of-concept study demonstrated the efficacy of this coculture model in evaluating testosterone-mediated androgen receptor responses in the presence of human liver metabolism. This liver-organ coculture system provides a practical, higher-throughput testing platform for metabolism-dependent bioactivity assessment of drugs/chemicals to better recapitulate the biological effects and potential toxicity of human exposures.
    Mesh-Begriff(e) Humans ; Coculture Techniques ; Liver/drug effects ; Liver/metabolism ; High-Throughput Screening Assays ; Hepatocytes/drug effects ; Hepatocytes/metabolism ; Toxicity Tests/methods ; Cell Line ; Biomarkers/metabolism ; Xenobiotics/toxicity
    Chemische Substanzen Biomarkers ; Xenobiotics
    Sprache Englisch
    Erscheinungsdatum 2024-02-06
    Erscheinungsland United States
    Dokumenttyp Journal Article
    ZDB-ID 1420885-4
    ISSN 1096-0929 ; 1096-6080
    ISSN (online) 1096-0929
    ISSN 1096-6080
    DOI 10.1093/toxsci/kfae018
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  5. Artikel ; Online: Beyond AOPs: A Mechanistic Evaluation of NAMs in DART Testing.

    Rajagopal, Ramya / Baltazar, Maria T / Carmichael, Paul L / Dent, Matthew P / Head, Julia / Li, Hequn / Muller, Iris / Reynolds, Joe / Sadh, Kritika / Simpson, Wendy / Spriggs, Sandrine / White, Andrew / Kukic, Predrag

    Frontiers in toxicology

    2022  Band 4, Seite(n) 838466

    Abstract: New Approach Methodologies (NAMs) promise to offer a unique opportunity to enable human-relevant safety decisions to be made without the need for animal testing in the context of exposure-driven Next Generation Risk Assessment (NGRA). Protecting human ... ...

    Abstract New Approach Methodologies (NAMs) promise to offer a unique opportunity to enable human-relevant safety decisions to be made without the need for animal testing in the context of exposure-driven Next Generation Risk Assessment (NGRA). Protecting human health against the potential effects a chemical may have on embryo-foetal development and/or aspects of reproductive biology using NGRA is particularly challenging. These are not single endpoint or health effects and risk assessments have traditionally relied on data from Developmental and Reproductive Toxicity (DART) tests in animals. There are numerous Adverse Outcome Pathways (AOPs) that can lead to DART, which means defining and developing strict testing strategies for every AOP, to predict apical outcomes, is neither a tenable goal nor a necessity to ensure NAM-based safety assessments are fit-for-purpose. Instead, a pragmatic approach is needed that uses the available knowledge and data to ensure NAM-based exposure-led safety assessments are sufficiently protective. To this end, the mechanistic and biological coverage of existing NAMs for DART were assessed and gaps to be addressed were identified, allowing the development of an approach that relies on generating data relevant to the overall mechanisms involved in human reproduction and embryo-foetal development. Using the knowledge of cellular processes and signalling pathways underlying the key stages in reproduction and development, we have developed a broad outline of endpoints informative of DART. When the existing NAMs were compared against this outline to determine whether they provide comprehensive coverage when integrated in a framework, we found them to generally cover the reproductive and developmental processes underlying the traditionally evaluated apical endpoint studies. The application of this safety assessment framework is illustrated using an exposure-led case study.
    Sprache Englisch
    Erscheinungsdatum 2022-03-07
    Erscheinungsland Switzerland
    Dokumenttyp Journal Article
    ISSN 2673-3080
    ISSN (online) 2673-3080
    DOI 10.3389/ftox.2022.838466
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  6. Artikel ; Online: Development of a human liver microphysiological coculture system for higher throughput chemical safety assessment

    Ip, Blanche C. / Madnick, Samantha J. / Zheng, Sophia / van Tongeren, Tessa C.A. / Hall, Susan J. / Li, Hui / Martin, Suzanne / Spriggs, Sandrine / Carmichael, Paul / Chen, Wei / Ames, David / Breitweiser, Lori A. / Pence, Heather E. / Bowling, Andrew J. / Johnson, Kamin J. / Cubberley, Richard / Morgan, Jeffrey R. / Boekelheide, Kim

    Toxicological sciences (2024) ; ISSN: 1096-6080

    2024  

    Abstract: Chemicals in the systemic circulation can undergo hepatic xenobiotic metabolism, generate metabolites, and exhibit altered toxicity compared with their parent compounds. This article describes a 2-chamber liver-organ coculture model in a higher- ... ...

    Abstract Chemicals in the systemic circulation can undergo hepatic xenobiotic metabolism, generate metabolites, and exhibit altered toxicity compared with their parent compounds. This article describes a 2-chamber liver-organ coculture model in a higher-throughput 96-well format for the determination of toxicity on target tissues in the presence of physiologically relevant human liver metabolism. This 2-chamber system is a hydrogel formed within each well consisting of a central well (target tissue) and an outer ring-shaped trough (human liver tissue). The target tissue chamber can be configured to accommodate a three-dimensional (3D) spheroid-shaped microtissue, or a 2-dimensional (2D) cell monolayer. Culture medium and compounds freely diffuse between the 2 chambers. Human-differentiated HepaRG liver cells are used to form the 3D human liver microtissues, which displayed robust protein expression of liver biomarkers (albumin, asialoglycoprotein receptor, Phase I cytochrome P450 [CYP3A4] enzyme, multidrug resistance-associated protein 2 transporter, and glycogen), and exhibited Phase I/II enzyme activities over the course of 17 days. Histological and ultrastructural analyses confirmed that the HepaRG microtissues presented a differentiated hepatocyte phenotype, including abundant mitochondria, endoplasmic reticulum, and bile canaliculi. Liver microtissue zonation characteristics could be easily modulated by maturation in different media supplements. Furthermore, our proof-of-concept study demonstrated the efficacy of this coculture model in evaluating testosterone-mediated androgen receptor responses in the presence of human liver metabolism. This liver-organ coculture system provides a practical, higher-throughput testing platform for metabolism-dependent bioactivity assessment of drugs/chemicals to better recapitulate the biological effects and potential toxicity of human exposures.
    Schlagwörter Life Science
    Thema/Rubrik (Code) 500
    Sprache Englisch
    Erscheinungsland nl
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  7. Artikel ; Online: Effect of Repeated Daily Dosing with 2,4-Dinitrochlorobenzene on Glutathione Biosynthesis and Nrf2 Activation in Reconstructed Human Epidermis.

    Spriggs, Sandrine / Sheffield, David / Olayanju, Adedamola / Kitteringham, Neil R / Naisbitt, Dean J / Aleksic, Maja

    Toxicological sciences : an official journal of the Society of Toxicology

    2016  Band 154, Heft 1, Seite(n) 5–15

    Abstract: Glutathione (GSH) plays a major role in skin detoxification processes due to its ability to conjugate electrophilic exogenous compounds with, and sometimes without, catalysis by glutathione-s-transferase (GST). GST activity has been demonstrated both in ... ...

    Abstract Glutathione (GSH) plays a major role in skin detoxification processes due to its ability to conjugate electrophilic exogenous compounds with, and sometimes without, catalysis by glutathione-s-transferase (GST). GST activity has been demonstrated both in skin and in most in vitro skin equivalents but so far studies have focussed on chemical clearance (conjugate identification and rate of conjugation) and did not consider the GSH lifecycle (conjugation, recycling, synthesis). We used the model skin sensitizer 2,4-dinitrochlorobenzene (DNCB) to investigate the effects of chemical exposure on GSH lifecycle in reconstructed human epidermis (RHE). We demonstrated that the RHE model is suitable to carry out repeated cycles of 2-h exposure to DNCB over a 3-day period. After each exposure to DNCB, the level of GSH is diminished in a dose dependent manner. After a 22-h recovery period, GSH is replenished back to initial levels. Accumulation of the nuclear factor E2-related factor 2 (Nrf2) in the cytosol also occurs within the 2 h of exposure to DNCB but returns to baseline during each recovery period, demonstrating that activation of the Nrf2 signaling pathway offers a rapid response to chemical stress. The amount of dinitrophenyl-glutathione (DNP-SG) formed with DNCB (1) increased between the first and second exposure and (2) reached a plateau between the second and third exposure. Collectively, these data suggest that the metabolic capacity of skin may not be fixed in time but defence mechanisms might be activated in response to exposure to exogenous compounds, resulting in their accelerated clearance.
    Mesh-Begriff(e) Dinitrochlorobenzene/toxicity ; Epidermis/drug effects ; Glutathione/biosynthesis ; Humans ; NF-E2-Related Factor 2/metabolism ; Tissue Culture Techniques
    Chemische Substanzen Dinitrochlorobenzene ; NF-E2-Related Factor 2 ; NFE2L2 protein, human ; Glutathione (GAN16C9B8O)
    Sprache Englisch
    Erscheinungsdatum 2016-08-04
    Erscheinungsland United States
    Dokumenttyp Journal Article
    ZDB-ID 1420885-4
    ISSN 1096-0929 ; 1096-6080
    ISSN (online) 1096-0929
    ISSN 1096-6080
    DOI 10.1093/toxsci/kfw140
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