Overview on Current Status and Combination of Test Methods

Chapter

Abstract

During the last years significant progress has been made in the development and validation of animal-free methods for assessing skin sensitization. Despite these advances, more efforts are still needed to refine the existing methods and to further develop new methods that lead to an improved awareness of the real mechanisms of a chemical in triggering a sensitization reaction in exposed human beings. An important observation is that detailed analysis of chemicals producing misleading results may help to define limitations of the respective tests methods and the databases derived from animal studies. Already several testing strategies have emerged that combine the data different test methods. At the moment, the usefulness of these strategies in the context of integrated approaches to testing and assessment (IATA) for skin sensitization is being evaluated. A key remaining challenge is the evaluation of chemical sensitizer potency using in vitro methods; however, based on the ongoing developments, it is expected that this may become reality in the near future.

References

  1. 1.
    Ankley GT, Bennett RS, Erickson RJ, Hoff DJ, Hornung MW, Johnson RD, Mount DR, Nichols JW, Russom CL, Schmieder PK, Serrano JA, Tietge JE, Villeneuve DL. Adverse outcome pathways: a conceptual framework to support ecotoxicology research and risk assessment. Environ Toxicol Chem. 2010;29:730–41.CrossRefGoogle Scholar
  2. 2.
    OECD. Proposal for a template and guidance on developing and assessing the completeness of adverse outcome pathways. 2012.Google Scholar
  3. 3.
    OECD. Guidance document on developing and assessing adverse outcome pathways. 2013.Google Scholar
  4. 4.
    US-EPA. Guidelines for carcinogen risk assessment. Washington, DC: U.S. Environmental Protection Agency; 2005.Google Scholar
  5. 5.
    US National Research Council. Toxicity testing in the 21st century:a vision and a strategy. Washington, DC: The National Academies Press; 2007.Google Scholar
  6. 6.
    Berg N, DeWever B, Fuchs HW, Gaca M, Krul C, Roggen EL. Toxicology in the 21st century – working our way towards a visionary reality. Toxicol In Vitro. 2011;25:874–81.CrossRefGoogle Scholar
  7. 7.
    Rovida C, Ryan C, Cinelli S, Basketter D, Dearman R, Kimber I. The local lymph node assay (LLNA). Curr Protoc Toxicol. 2012;20:1–14.Google Scholar
  8. 8.
    Basketter DA, Kimber I. Contact hypersensitivity. In: McQueen CA, editor. Comprehensive toxicology, vol. 5. 2nd ed. Kidlington: Elsevier; 2010. p. 397–411.CrossRefGoogle Scholar
  9. 9.
    Corsini E, Roggen EL. Immunotoxicology: opportunities for non-animal test development. Altern Lab Anim. 2009;37:387–97.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Roggen EL. Application of the acquired knowledge and implementation of the Sens-it-iv toolbox for identification and classification of skin and respiratory sensitizers. Toxicol In Vitro. 2012;27:1122–6. doi: 10.1016/j.tiv.2012-09.019.CrossRefPubMedGoogle Scholar
  11. 11.
    OECD. The adverse outcome pathway for skin sensitization initiated by covalent binding to proteins. Part 1: scientific evidence, series on testing and assessment. 2013;168.Google Scholar
  12. 12.
    Basketter D, Pease C, Kasting G, Kimber I, Casati S, Cronin M, et al. Skin sensitization and epidermal disposition: the relevance of assessment. Altern Lab Anim. 2007;35:137–54.PubMedGoogle Scholar
  13. 13.
    Smith CK, Hotchkiss SAM. Allergic contact dermatitis: chemical and metabolic mechanisms. London: Taylor & Francis Ltd; 2001. doi: 10.1034/j.1600-0536.2001.450224-2.x.CrossRefGoogle Scholar
  14. 14.
    Chipinda, I, Hettick JM, Siegel PD. Haptenation: chemical reactivity and protein binding. J Allergy. 2011; 839682. doi: 10.1155/2011/839682CrossRefGoogle Scholar
  15. 15.
    Albrekt AS, Johansson H, Börje A, Borrebaeck CAK, Lindstedt M. Differentially regulated signalling pathways in MUTZ-3 cells stimulated with skin sensitizers. BMC Pharmacol Toxicol. 2014.; http://www.biomedcentral.com/2050-6511/15/5.
  16. 16.
    Chipinda I, Ajibola RO, Morakinyo MK, Ruwona TB, Simoyi RH, Siegel PD. Rapid and simple kinetics screening assay for electrophilic dermal sensitizers using nitrobenzenethiol. Chem Res Toxicol. 2010;23:918–25.CrossRefGoogle Scholar
  17. 17.
    Gerberick F, Aleksic M, Basketter D, Casati S, Karlberg AT, Kern P, et al. Chemical reactivity measurement and the predictive identification of skin sensitisers. The report and recommendations of ECVAM workshop 64. Altern Lab Anim. 2008;36:215–42.PubMedGoogle Scholar
  18. 18.
    Gerberick F, Troutman J, Foertsch L, Vasallo JD, Quijano M, Dobson RLM, et al. Investigation of peptide reactivity of pro-hapten skin sensitizers using a peroxidase-peroxide oxidation system. Toxicol Sci. 2009;112:164–74.CrossRefGoogle Scholar
  19. 19.
    Lalko JF, Dearman RJ, Gerberick GF, Troutman JA, Api AM, Kimber I. Reactivity of chemical respiratory allergens in the peroxidase peptide reactivity assay. Toxicol In Vitro. 2012;27:651–61.CrossRefGoogle Scholar
  20. 20.
    Manchanda T, Hess D, Dale L, Ferguson SG, Rieder MJ. Haptenation of sulfonamide reactive metabolites to cellular proteins. Mol Pharmacol. 2002;62:1011–26.CrossRefGoogle Scholar
  21. 21.
    Corsini E, Galbiati V, Mitjans M, Galli CL, Marinovich M. NCTC 2544 and IL-18 production: a tool for the identification of contact allergens. Toxicol In Vitro. 2013;27:1127–34.CrossRefGoogle Scholar
  22. 22.
    Corsini E, Galbiati V, Nikitovic D, Tsatsakis AFM. Role of oxidative stress in chemical allergens induced skin cells activation. Food Chem Toxicol. 2013;61:74–81.CrossRefGoogle Scholar
  23. 23.
    Ray PD, Huang BW, Tsuji Y. Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signalling. Cell Signal. 2012;24:981–90.CrossRefGoogle Scholar
  24. 24.
    Esser PR, Wölfle U, Dürr C, von Loewenich FD, Schempp CM, Freudenberg MA, et al. Contact sensitizers induce skin inflammation via ROS production and hyaluronic acid degradation. PLoS One. 2012;7:e41340.CrossRefGoogle Scholar
  25. 25.
    Martin SF, Dudda JC, Bachtanian E, Lembo A, Liller S, Durr C, et al. Toll-like receptor and IL-12 signaling control susceptibility to contact hypersensitivity. J Exp Med. 2008;205:2151–62.CrossRefGoogle Scholar
  26. 26.
    Antonopoulos C, Cumberbatch M, Mee JB, Dearman RJ, Wei X, Liew FY, et al. IL-18 is a key proximal mediator of contact hypersensitivity and allergen-induced Langerhans cell migration in murine epidermis. J Leukoc Biol. 2008;83:361–7.CrossRefGoogle Scholar
  27. 27.
    Emter R, van der Veen JW, Adamson G, Ezendam J, van Loveren H, Natsch A. Gene expression changes induced by skin sensitizers in the KeratinosensTM™ cell line: discriminating Nrf2-dependent and Nrf2-independent events. Toxicol In Vitro. 2013;27:2225–32.CrossRefGoogle Scholar
  28. 28.
    Migdal C, Botton J, El Ali Z, Azoury ME, Guldemann J, Gimenez-Arnau E, et al. Reactivity of chemical sensitizers toward amino acids in cellulo plays a role in the activation of the Nrf2-ARE pathway in human monocyte dendritic cells and the THP-1 cell line. Toxicol Sci. 2013;133:259–74.CrossRefGoogle Scholar
  29. 29.
    Dos Santos GG, Spiekstra SW, Sampat-Sardjoepersad SC, Reinders J, Scheper RJ, Gibbs S. A potential in vitro epidermal equivalent assay to determine sensitizer potency. Toxicol In Vitro. 2011;25:347–57.CrossRefGoogle Scholar
  30. 30.
    Gibbs S, Corsini E, Spiekstra SW, Galbiati V, Fuchs HW, Degeorge G, Troese M, Hayden P, Deng W, Roggen EL. An epidermal equivalent assay for identification and ranking potency of contact sensitizers. Toxicol Appl Pharmacol. 2013;15:529–41.CrossRefGoogle Scholar
  31. 31.
    van der Veen JW, Pronk TE, van Loveren H, Ezendam J. Applicability of a keratinocyte gene signature to predict skin sensitizing potential. Toxicol In Vitro. 2013;27:314–22.CrossRefGoogle Scholar
  32. 32.
    Roggen EL. In vitro approaches for detection of chemical sensitization. Basic Clin Pharmacol Toxicol. 2014;115:32–40.CrossRefGoogle Scholar
  33. 33.
    Tan JKH, O’Neil HC. Maturation requirements for dendritic cells in T cell stimulation leading to tolerance versus immunity. J Leukoc Biol. 2005;78:319–24.CrossRefGoogle Scholar
  34. 34.
    Johansson H, Lindstedt M, Albrekt AS, Borrebaeck CAK. A genomic biomarker signature can predict skin sensitizers using a cell-based in vitro alternative to animal tests. BMC Genomics. 2011;12:399–417.CrossRefGoogle Scholar
  35. 35.
    Ashikaga T, Yoshida Y, Hirota M, Yoneyama K, Itagaki H, Sakaguchi H, et al. Development of an in vitro skin sensitization test using human cell lines; human cell line activation test (h-CLAT). I. Optimization of the h-CLAT protocol. Toxicol In Vitro. 2006;20:767–73.CrossRefGoogle Scholar
  36. 36.
    Python F, Goebel C, Aeby P. Assessment of the U937 cell line for the detection of contact allergens. Toxicol Appl Pharmacol. 2007;220:113–24.CrossRefGoogle Scholar
  37. 37.
    Neves BM, Cruz MT, Francisco V, Gonçalo M, Figueiredo A, Duarte CB, Lopes MC. Differential modulation of CXCR4 and CD40 protein levels by skin sensitizers and irritants in the FSDC cell line. Toxicol Lett. 2008;177:74–82.CrossRefGoogle Scholar
  38. 38.
    Lambrechts N, Nelissen I, Van Tendeloo V, Witters H, Van Den Heuvel R, Hooyberghs J, Schoeters G. Functionality and specificity of gene markers for skin sensitization in dendritic cells. Toxicol Lett. 2011;203:106–10.CrossRefGoogle Scholar
  39. 39.
    Lundberg K, Albrekt A-S, Nelissen I, Santegoets S, de Gruijl TD, Gibbs S, et al. Transcriptional profiling of human dendritic cell populations and models - unique profiles of in vitro dendritic cells and implications on functionality and applicability. PLoS One. 2013;8:e52875.CrossRefGoogle Scholar
  40. 40.
    Thierse HJ, Budde P, Dietz L, Ohnesorge S, Eikelmeier S, Conde M, Zucht HD, Schulz-Knappe P. Proteomic identification of allergen-regulated proteins and allergen-protein interaction networks in assisting biomarker and assay development. In: Roggen EL, Weltzien H-U, Hermans H, editors. Progress towards novel testing strategies for in vitro assessment of allergens. Kerala: Transworld Research Network; 2011. p. 145–66.Google Scholar
  41. 41.
    Villablanca EJ, Russo V, Mora JR. Dendritic cell migration and lymphocyte homing imprinting. Histol Histopathol. 2008;23:897–910.PubMedGoogle Scholar
  42. 42.
    Ouwehand K, Scheper RJ, de Gruijl TD, Gibbs S. Epidermis-to dermis migration of immature Langerhans cells upon topical irritant exposure is dependent on CCL2 and CCL5. Eur J Immunol. 2012;40:2026–34.CrossRefGoogle Scholar
  43. 43.
    Ouwehand K, Spiekstra SW, Waaijman T, Scheper RJ, de Gruijl TD, Gibbs S. Langerhans cells derived from a human cell line in a full-thickness skin equivalent undergo allergen-induced maturation and migration. Tech Adv. 2011;90:1028–33.Google Scholar
  44. 44.
    Rees B, Spiekstra SW, Carfi M, Ouwehand K, Williams CA, Corsini E, et al. Inter-laboratory study of the in vitro DC migration assay for identification of contact allergens. Toxicol In Vitro. 2011;25:2124–3445.CrossRefGoogle Scholar
  45. 45.
    Jelley-Gibbs DM, Strutt TM, McKinstry KK, Swain SL. Influencing the fates of CD4 T cells on the path to memory: lessons from influenza. Immunol Cell Biol. 2008;86:343–52.CrossRefGoogle Scholar
  46. 46.
    Mempel TR, Henricksen SE, von Andrian UH. T-cell priming by dendritic cells in lymph nodes occurs in three distinct phases. Nature. 2004;8:154–9.CrossRefGoogle Scholar
  47. 47.
    Xu H, Dilulio NA, Fairchild RL. T cell populations primed by hapten sensitization in contact sensitivity are distinguished by polarized patterns of cytokine production: interferon gamma-producing(Tc1) effector CD8+ T cells and interleukin (IL) 4/IL-10 negative regulatory CD4+ T cells. J Exp Med. 1996;183:1001–12.CrossRefGoogle Scholar
  48. 48.
    Albanesi C, Scarponi C, Cavani A, Federici M, Nasorri F, Girolomoni G. Interleukin-17 is produced by both Th1 and Th2 lymphocytes, and modulates interferon-gamma and interleukin-4-induced activation of human keratinocytes. J Invest Dermatol. 2000;115:81–7.CrossRefGoogle Scholar
  49. 49.
    Nakae S, Komiyama Y, Nambu A, Sudo K, Iwase M, Homma I, et al. Antigen-specific T cell sensitization is impaired in IL-17-deficient mice, causing suppression of allergic cellular and humoral responses. Immunity. 2002;17:375–87.CrossRefGoogle Scholar
  50. 50.
    Richter A, Schmucker SS, Esser PR, Traska V, Weber V, Dietz L, et al. Human T cell priming assay (hTCPA) for the identification of contact allergens based on naive T cells and DC–IFN-c and TNF-a readout. Toxicol In Vitro. 2013;27:1180–5.CrossRefGoogle Scholar
  51. 51.
    Roggen EL, Lindstedt M, Borrebaeck C, Verheyen GR. Interactions between dendritic cells and epithelial cells in allergic disease. Toxicol Lett. 2006;162:71–82.CrossRefGoogle Scholar
  52. 52.
    Adler S, Basketter D, Creton S, Pelkonen O, van Benthem J, Zuang V, Andersen KE, Angers-Loustau A, Aptula A, Bal-Price A, Benfenati E, Bernauer U, Bessems J, Bois FY, Boobis A, Brandon E, Bremer S, Broschard T, Casati S, Coecke S, Corvi R, Cronin M, Daston G, Dekant W, Felter S, Grignard E, Gundert-Remy U, Heinonen T, Kimber I, Kleinjans J, Komulainen H, Kreiling R, Kreysa J, Leite SB, Loizou G, Maxwell G, Mazzatorta P, Munn S, Pfuhler S, Phrakonkham P, Piersma A, Poth A, Prieto P, Repetto G, Rogiers V, Schoeters G, Schwarz M, Serafimova R, Tähti H, Testai E, van Delft J, van Loveren H, Vinken M, Worth A, Zaldivar JM. Alternative (non-animal) methods for cosmetics testing: current status and future prospects-2010. Arch Toxicol. 2011;85:367–485.CrossRefGoogle Scholar
  53. 53.
    Kinsner-Ovaskainen A, Rzepka R, Rudowski R, Coecke S, Cole T, Prieto P. Acutoxbase, aninnovative database for in vitro acute toxicity studies. Toxicol In Vitro. 2009;23:476–85.CrossRefGoogle Scholar
  54. 54.
    OECD. Guidance document on the reporting of defined approaches to be used within integrated approaches for testing and assessment - ENV/JM/HA(2016)10. 2016.Google Scholar
  55. 55.
    OECD. Guidance document on the reporting of defined approaches and individual information sources to be used within integrated approaches to testing and assessment (IATA) for skin sensitization - ENV/JM/HA(2016)11. 2016.Google Scholar
  56. 56.
    Bauch C, Kolle SN, Ramirez T, Eltze T, Fabian E, Mehling A, Teubner W, van Ravenzwaay B, Landsiedel R. Putting the parts together: combining in vitro methods to test for skin sensitizing potential. Regulat Toxicol Pharmacol. 2012;63:489–504.CrossRefGoogle Scholar
  57. 57.
    Gomes C, Hicham N, Thomas M, Ibanez F, Collin JF, Saporta G. Stacking prediction for a binary outcome. In: Compstat, Aug 2012, Limassol, Cyprus. 2012; pp.271–282.Google Scholar
  58. 58.
    Natsch A, Ryan CA, Foertsch L, Emter R, Jaworska J, Gerberick F, Kern P. A dataset on 145 chemicals tested in alternative assays for skin sensitization undergoing prevalidation. J Appl Toxicol. 2013;33(11):1337–52. doi: 10.1002/jat.2868.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Nukada Y, Miyazawa M, Kazutoshi S, Sakaguchi H, Nishiyama N. Data integration of non-animal tests for the development of a test battery to predict the skin sensitizing potential and potency of chemicals. Toxicol In Vitro. 2013;27(2):609–18.CrossRefGoogle Scholar
  60. 60.
    Jaworska J, Dancik Y, Kern P, Gerberick F, Natsch A. Bayesian integrated testing strategy to assess skin sensitization potency: from theory to practice. J Appl Toxicol. 2013;33(11):1353–64. doi: 10.1002/jat.2869.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Jaworska J, Harol A, Kern PS, Gerberick GF. Integrating non-animal test information into an adaptive testing strategy - skin sensitization proof of concept case. ALTEX. 2011;28(3):211–25.CrossRefGoogle Scholar
  62. 62.
    Jaworska J, Natsch A, Ryan C, Strickland J, Ashikaga T, Miyazawa M. Bayesian integrated testing strategy (ITS) for skin sensitization potency assessment: a decision support system for quantitative weight of evidence and adaptive testing strategy. Arch Toxicol. 2015;89(12):2355–83.CrossRefGoogle Scholar
  63. 63.
    van der Veen JW, Rorije E, Emter R, Natsch A, van Loveren H, Ezendam J. Evaluating the performance of integrated approaches for hazard identification of skin sensitizing chemicals. Regul Toxicol Pharmacol. 2014;69:371–9.CrossRefGoogle Scholar
  64. 64.
    Patlewicz G, Casati S, Basketter DA, Asturiol D, Roberts DW, Lepoittevin JP, Worth AP, Aschberger K. Can currently available non-animal methods detect pre and pro-haptens relevant for skin sensitization? Regul Toxicol Pharmacol. 2016;82:147–55. Aug 26 S0273-2300(16)30228–8CrossRefGoogle Scholar
  65. 65.
    Natsch A, Emter R, Gfeller H, Haupt T, Ellis G. Predicting skin sensitizer potency based on in vitro data from KeratinoSens and kinetic peptide binding: global versus domain-based assessment. Toxicol Sci. 2015;143(2):319–32. doi: 10.1093/toxsci/kfu229.CrossRefPubMedGoogle Scholar
  66. 66.
    Urbisch D, Mehling A, Guth K, Ramirez T, Honarvar N, Kolle S, Landsiedel R, Jaworska J, Kern PS, Gerberick F, Natsch A, Emter R, Ashikaga T, Miyazawa M, Sakaguchi H. Assessing skin sensitization hazard in mice and men using non-animal test methods. Regul Toxicol Pharmacol. 2015;71:337–51.CrossRefGoogle Scholar
  67. 67.
    Hirota M, Fukui S, Okamoto K, Kurotani S, Imai N, Fujishiro M, Kyotani D, Kato Y, Kasahara T, Fujita M, Toyoda A, Sekiya D, Watanabe S, Seto H, Takenouchi O, Ashikaga T, Miyazawa M. Evaluation of combinations of in vitro sensitization test descriptors for the artificial neural network-based risk assessment model of skin sensitization. J Appl Toxicol. 2015;35:1333–47.CrossRefGoogle Scholar
  68. 68.
    Takenouchi O, Fukui S, Okamoto K, Kurotani S, Imai N, Fujishiro M, Kyotani D, Kato Y, Kasahara T, Fujita M, Toyoda A, Sekiya D, Watanabe S, Seto H, Hirota M, Ashikaga T, Miyazawa M. (2015) test battery with the human cell line activation test, direct peptide reactivity assay and DEREK based on a 139 chemical data set for predicting skin sensitizing potential and potency of chemicals. J Appl Toxicol. 2015;35(11):1318–32.CrossRefGoogle Scholar
  69. 69.
    Strickland J, Zang Q, Paris M, Lehmann DM, Allen D, Choksi N, Matheson J, Jacobs A, Casey W, Kleinstreuer N.Multivariate models for prediction of human skin sensitization hazard. J Appl Toxicol. 2016; doi:  10.1002/jat.3366.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Asturiol D, Casati S, Worth A. Consensus of classification trees for skin sensitisation hazard prediction. Toxicol In Vitro. 2016;36:197–209. doi: 10.1016/j.tiv.2016.07.014.CrossRefPubMedGoogle Scholar
  71. 71.
    Strickland J, Zang Q, Kleinstreuer N, Paris M, Lehmann DM, Choksi N, Matheson J, Jacobs A, Lowit A, Allen D, Casey W. Integrated decision strategies for skin sensitization hazard. J Appl Toxicol. 2016;36(9):1150–62. doi: 10.1002/jat.3281.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.3Rs Management and Consulting ApSKongens LyngbyDenmark

Personalised recommendations