Non-animal methods to predict skin sensitization (I): the Cosmetics Europe database*

Abstract Cosmetics Europe, the European Trade Association for the cosmetics and personal care industry, is conducting a multi-phase program to develop regulatory accepted, animal-free testing strategies enabling the cosmetics industry to conduct safety assessments. Based on a systematic evaluation of test methods for skin sensitization, five non-animal test methods (DPRA (Direct Peptide Reactivity Assay), KeratinoSensTM, h-CLAT (human cell line activation test), U-SENSTM, SENS-IS) were selected for inclusion in a comprehensive database of 128 substances. Existing data were compiled and completed with newly generated data, the latter amounting to one-third of all data. The database was complemented with human and local lymph node assay (LLNA) reference data, physicochemical properties and use categories, and thoroughly curated. Focused on the availability of human data, the substance selection resulted nevertheless resulted in a high diversity of chemistries in terms of physico-chemical property ranges and use categories. Predictivities of skin sensitization potential and potency, where applicable, were calculated for the LLNA as compared to human data and for the individual test methods compared to both human and LLNA reference data. In addition, various aspects of applicability of the test methods were analyzed. Due to its high level of curation, comprehensiveness, and completeness, we propose our database as a point of reference for the evaluation and development of testing strategies, as done for example in the associated work of Kleinstreuer et al. We encourage the community to use it to meet the challenge of conducting skin sensitization safety assessment without generating new animal data.

[1]  Janine Ezendam,et al.  State of the art in non-animal approaches for skin sensitization testing: from individual test methods towards testing strategies , 2016, Archives of Toxicology.

[2]  David W. Roberts,et al.  Chemical applicability domain of the local lymph node assay (LLNA) for skin sensitisation potency. Part 4. Quantitative correlation of LLNA potency with human potency , 2018, Regulatory toxicology and pharmacology : RTP.

[3]  Gribaldo Laura,et al.  State-of-the-art and new options to assess T cell activation by skin sensitizers: Cosmetics Europe Workshop. , 2017 .

[4]  G Frank Gerberick,et al.  Investigation of peptide reactivity of pro-hapten skin sensitizers using a peroxidase-peroxide oxidation system. , 2009, Toxicological sciences : an official journal of the Society of Toxicology.

[5]  Anne Marie Api,et al.  Chemical applicability domain of the Local Lymph Node Assay (LLNA) for skin sensitisation potency. Part 2. The biological variability of the murine Local Lymph Node Assay (LLNA) for skin sensitisation. , 2016, Regulatory toxicology and pharmacology : RTP.

[6]  Claude Auriault,et al.  Genes specifically modulated in sensitized skins allow the detection of sensitizers in a reconstructed human skin model. Development of the SENS-IS assay. , 2015, Toxicology in vitro : an international journal published in association with BIBRA.

[7]  Sebastian Hoffmann,et al.  Intra- and inter-laboratory reproducibility and accuracy of the LuSens assay: A reporter gene-cell line to detect keratinocyte activation by skin sensitizers. , 2016, Toxicology in vitro : an international journal published in association with BIBRA.

[8]  J. Hennen,et al.  Keratinocytes improve prediction of sensitization potential and potency of chemicals with THP-1 cells. , 2016, ALTEX.

[9]  Rob J. Vandebriel,et al.  Non-animal sensitization testing: State-of-the-art , 2010, Critical reviews in toxicology.

[10]  Sebastian Hoffmann,et al.  A feasibility study developing an integrated testing strategy assessing skin irritation potential of chemicals. , 2008, Toxicology letters.

[11]  S Dimitrov,et al.  Accounting for data variability, a key factor in in vivo/in vitro relationships: application to the skin sensitization potency (in vivo LLNA versus in vitro DPRA) example , 2016, Journal of applied toxicology : JAT.

[12]  Takao Ashikaga,et al.  Prediction of skin sensitization potency of chemicals by human Cell Line Activation Test (h-CLAT) and an attempt at classifying skin sensitization potency. , 2012, Toxicology in vitro : an international journal published in association with BIBRA.

[13]  G Frank Gerberick,et al.  Allergic Contact Dermatitis , 1998, Springer Berlin Heidelberg.

[14]  E. Buehler,et al.  DELAYED CONTACT HYPERSENSITIVITY IN THE GUINEA PIG. , 1965, Archives of dermatology.

[15]  Petra S Kern,et al.  Mechanistic applicability domain classification of a local lymph node assay dataset for skin sensitization. , 2007, Chemical research in toxicology.

[16]  Coralie Dumont,et al.  Analysis of the Local Lymph Node Assay (LLNA) variability for assessing the prediction of skin sensitisation potential and potency of chemicals with non-animal approaches. , 2016, Toxicology in vitro : an international journal published in association with BIBRA.

[17]  G Frank Gerberick,et al.  Development of a peptide reactivity assay for screening contact allergens. , 2004, Toxicological sciences : an official journal of the Society of Toxicology.

[18]  Martina Klaric,et al.  Systematic evaluation of non-animal test methods for skin sensitisation safety assessment. , 2015, Toxicology in vitro : an international journal published in association with BIBRA.

[19]  A Worth,et al.  Consensus of classification trees for skin sensitisation hazard prediction. , 2016, Toxicology in vitro : an international journal published in association with BIBRA.

[20]  Sebastian Hoffmann,et al.  LLNA variability: An essential ingredient for a comprehensive assessment of non-animal skin sensitization test methods and strategies. , 2015, ALTEX.

[21]  I Kimber,et al.  The local lymph node assay: developments and applications. , 1994, Toxicology.

[22]  Malin Lindstedt,et al.  From genome-wide arrays to tailor-made biomarker readout - Progress towards routine analysis of skin sensitizing chemicals with GARD. , 2016, Toxicology in vitro : an international journal published in association with BIBRA.

[23]  Wolfgang Uter,et al.  Acceptable risk of contact allergy in the general population assessed by CE-DUR--a method to detect and categorize contact allergy epidemics based on patient data. , 2009, Regulatory toxicology and pharmacology : RTP.

[24]  Andreas Natsch,et al.  Predicting skin sensitizer potency based on in vitro data from KeratinoSens and kinetic peptide binding: global versus domain-based assessment. , 2015, Toxicological sciences : an official journal of the Society of Toxicology.

[25]  David Allen,et al.  An Integrated Chemical Environment to Support 21st-Century Toxicology , 2017, Environmental health perspectives.

[26]  Hiroshi Itagaki,et al.  A Comparative Evaluation of In Vitro Skin Sensitisation Tests: The Human Cell-line Activation Test (h-CLAT) versus the Local Lymph Node Assay (LLNA) , 2010, Alternatives to laboratory animals : ATLA.

[27]  Sebastian Hoffmann,et al.  Diagnosis: toxic!--trying to apply approaches of clinical diagnostics and prevalence in toxicology considerations. , 2005, Toxicological sciences : an official journal of the Society of Toxicology.

[28]  Anne Marie Api,et al.  Fragrances Categorized According to Relative Human Skin Sensitization Potency , 2017, Dermatitis.

[29]  I Kimber,et al.  Potency values from the local lymph node assay: application to classification, labelling and risk assessment. , 2010, Regulatory toxicology and pharmacology : RTP.

[30]  Setsuya Aiba,et al.  Optimization of the IL-8 Luc assay as an in vitro test for skin sensitization. , 2015, Toxicology in vitro : an international journal published in association with BIBRA.

[31]  I. Kimber,et al.  Use of the local lymph node assay for the estimation of relative contact allergenic potency , 2000, Contact dermatitis.

[32]  Emanuela Corsini,et al.  Transfer of a two-tiered keratinocyte assay: IL-18 production by NCTC2544 to determine the skin sensitizing capacity and epidermal equivalent assay to determine sensitizer potency. , 2013, Toxicology in vitro : an international journal published in association with BIBRA.

[33]  Grace Patlewicz,et al.  Electrophilic chemistry related to skin sensitization. Reaction mechanistic applicability domain classification for a published data set of 106 chemicals tested in the mouse local lymph node assay. , 2007, Chemical research in toxicology.

[34]  Nathalie Alépée,et al.  The Myeloid U937 Skin Sensitization Test (U-SENS) addresses the activation of dendritic cell event in the adverse outcome pathway for skin sensitization. , 2015, Toxicology in vitro : an international journal published in association with BIBRA.

[35]  Silke Gabbert,et al.  The borderline range of toxicological methods: Quantification and implications for evaluating precision. , 2017, ALTEX.

[36]  Takao Ashikaga,et al.  Predictive performance of the human Cell Line Activation Test (h-CLAT) for lipophilic chemicals with high octanol-water partition coefficients. , 2013, The Journal of toxicological sciences.

[37]  Silvia Casati,et al.  Can currently available non-animal methods detect pre and pro-haptens relevant for skin sensitization? , 2016, Regulatory toxicology and pharmacology : RTP.

[38]  H. Sakaguchi,et al.  Development of an in vitro skin sensitization test using human cell lines: the human Cell Line Activation Test (h-CLAT). I. Optimization of the h-CLAT protocol. , 2006, Toxicology in vitro : an international journal published in association with BIBRA.

[39]  Antony J. Williams,et al.  In Silico Prediction of Physicochemical Properties of Environmental Chemicals Using Molecular Fingerprints and Machine Learning , 2017, J. Chem. Inf. Model..

[40]  A M Kligman,et al.  The identification of contact allergens by animal assay. The guinea pig maximization test. , 1970, The Journal of investigative dermatology.

[41]  Peter Fantke,et al.  Exploring consumer exposure pathways and patterns of use for chemicals in the environment , 2015, Toxicology reports.

[42]  Petra S Kern,et al.  Assessing skin sensitization hazard in mice and men using non-animal test methods. , 2015, Regulatory toxicology and pharmacology : RTP.

[43]  João Barroso,et al.  Categorization of Chemicals According to Their Relative Human Skin Sensitizing Potency , 2014, Dermatitis : contact, atopic, occupational, drug.

[44]  G. Patlewicz,et al.  An evaluation of the implementation of the Cramer classification scheme in the Toxtree software , 2008, SAR and QSAR in environmental research.

[45]  G Frank Gerberick,et al.  Local lymph node assay (LLNA) for detection of sensitization capacity of chemicals. , 2007, Methods.

[46]  Petra Kern,et al.  A dataset on 145 chemicals tested in alternative assays for skin sensitization undergoing prevalidation , 2013, Journal of applied toxicology : JAT.

[47]  Andreas Natsch,et al.  Performance of a novel keratinocyte-based reporter cell line to screen skin sensitizers in vitro. , 2010, Toxicology and applied pharmacology.

[48]  C Piroird,et al.  Prospective multicentre study of the U-SENS test method for skin sensitization testing. , 2015, Toxicology in vitro : an international journal published in association with BIBRA.

[49]  Bertrand Desprez,et al.  Non-animal methods to predict skin sensitization (II): an assessment of defined approaches** , 2018, Critical reviews in toxicology.

[50]  Hervé Groux,et al.  SENS-IS, a 3D reconstituted epidermis based model for quantifying chemical sensitization potency: Reproducibility and predictivity results from an inter-laboratory study. , 2016, Toxicology in vitro : an international journal published in association with BIBRA.