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Non-animal test methods for predicting skin sensitization potentials

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Abstract

Contact allergies are complex diseases, and it is estimated that 15–20 % of the general population suffers from contact allergy, with increasing prevalence. Evaluation of the sensitization potential of a substance is usually carried out in animal models. Nowadays, there is much interest in reducing and ultimately replacing current animal tests. Furthermore, as of 2013, the EU has posed a ban on animal testing of cosmetic ingredients that includes skin sensitization. Therefore, predictive and robust in vitro tests are urgently needed. In order to establish alternatives to animal testing, the in vitro tests must mimic the very complex interactions between the sensitizing chemical and the different parts of the immune system. This review article summarizes recent efforts to develop in vitro tests for predicting skin sensitizers. Cell-based assays, in chemico methods and, to a lesser extent, in silico methods are presented together with a discussion of their current status. With considerable progress having been achieved during the last years, the rationale today is that data from different non-animal test methods will have to be combined in order to obtain reliable hazard and potency information on potential skin sensitizers.

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References

  • Ackermann K, Borgia SL, Korting HC, Mewes KR, Schäfer-Korting M (2010) The Phenion full-thickness skin model for percutaneous absorption testing. Skin Pharmacol Physiol 23:105–112

    PubMed  CAS  Google Scholar 

  • Ade N, Martinozzi-Teissier S, Pallardy M, Rousset F (2006) Activation of U937 cells by contact sensitizers: CD86 expression is independent of apoptosis. J Immunotoxicol 3:189–197

    PubMed  CAS  Google Scholar 

  • Ade N, Leon F, Pallardy M, Peiffer J-L, Kerdine-Romer S, Tissier M-H, Bonnet P-A, Fabre I, Ourlin J-C (2009) HMOX1 and NQO1 genes are upregulated in response to contact sensitisers in dendritic cells and THP-1 cells line: role of the Keap1/Nrf2 pathway. Toxicol Sci 107:451–460

    PubMed  CAS  Google Scholar 

  • 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 (2011) Alternative (non-animal) methods for cosmetics testing: current status and future prospects-2010. Arch Toxicol 85:367–485

    PubMed  CAS  Google Scholar 

  • Aeby P, Ashikaga T, Bessou-Touya S, Schepky A, Gerberick F, Kern P, Marrec-Fairley M, Maxwell G, Ovigne J-M, Sakaguchi H, Reisinger, Tailhardat M, Martinozzi-Teissier S, Winkler P (2010) Identifying and characterizing chemical skin sensitizers without animal testing: Colipa’s research and method development program. Toxicol In Vitro 24:1465–1473

    PubMed  CAS  Google Scholar 

  • Aiba S, Manome H, Nakagawa S, Mollah ZU, Mizuashi M, Ohtani T, Yoshino Y, Tagami H (2003) P38 Mitogen activated protein kinase and extracellular signal-regulated kinases play distinct roles in the activation of dendritic cells by two representative haptens, NiCl2 and 2,4-dinitrochlorobenzene. J Invest Dermatol 120:390–399

    PubMed  CAS  Google Scholar 

  • Aleksic M, Thain E, Roger D, Saib O, Davies M, Li J, Aptula A, Zazzeroni R (2009) Reactivity profiling: covalent modification of single nucleophile peptides for skin sensitization risk assessment. Toxicol Sci 108:401–411

    PubMed  CAS  Google Scholar 

  • An S, Kim S, Huh Y, Lee TR, Kim H-K, Park K-L, Eun HC (2009) Expression of surface markers on the human monocytic leukaemia cell line, THP-1, as indicators for sensitizing potential of chemicals. Contact Dermatitis 60:185–192

    PubMed  CAS  Google Scholar 

  • Anderson SE, Siegel PD, Meade BJ (2011) The LLNA: a brief review of recent advances and limitations. J Allergy 2011, Article ID 424203. doi:10.1155/2011/424203

  • Antonopoulos C, Cumberbatch M, Mee JB, Dearman RJ, Wei X, Liew FY, Kimber I, Groves RW (2008) IL-18 is a key proximal mediator of contact hypersensitivity and allergen-induced Langerhans cell migration in murine epidermis. J Leukocyte Biol 83:361–367

    PubMed  CAS  Google Scholar 

  • Aptula AO, Roberts DW, Pease CK (2007) Haptens, prohaptens and prehaptens, or electrophiles and proelectrophiles. Contact Dermatitis 56:54–56

    PubMed  Google Scholar 

  • Arkusz J, Stepnik M, Sobala W, Dastych J (2010) Prediction of the contact sensitizing potential of chemicals using analysis of gene expression changes in human THP-1 monocytes. Toxicol Lett 199:51–99

    PubMed  CAS  Google Scholar 

  • Arts JH, Kuper CF (2007) Animal models to test respiratory allergy of low molecular weight chemicals: a guidance. Methods 41:61–71

    PubMed  CAS  Google Scholar 

  • Ashikaga T, Hoya M, Itagaki H, Kutumura Y, Aiba S (2002) Evaluation of CD86 expression and MHC class II molecular internalization in THP-1 human monocyte cells as predictive endpoints for contact sensitizers. Toxicol In Vitro 16:711–716

    PubMed  CAS  Google Scholar 

  • Ashikaga T, Yoshida Y, Hirota M, Yoneyama K, Itagaki H, Sakaguchi H, Miyazawa M, Ita Y, Suzuki H, Yoyoda H (2006) Development of an in vitro skin sensitization test using human cell lines: the human cell line activation test (h-CLAT).I. Optimisation of the h-CLAT protocol. Toxicol In Vitro 20:767–773

    PubMed  CAS  Google Scholar 

  • Ashikaga T, Sakaguchi H, Sono S, Kosaka N, Ishikawa M, Nukada Y, Miyazawa M, Ito Y, Nishiyama N, Itagaki H (2010) A comparative evaluation of in vitro skin sensitization tests: the human cell-line activation test (h-CLAT) versus the local lymph node assay (LLNA). Altern Lab Ani 38:275–284

    CAS  Google Scholar 

  • Auriault C, Mouhat L, Sabatier JM, Groux H (2011) Development of PEPT-IS®, a peptide-binding based assay for assessing chemical sensitization using lipocalin derived peptides. 8th World congress on alternatives & animal use in the life sciences, Montreal; ALTEX 28, Special Issue, Montreal 2011. http://www.wc8.ccac.ca/files/C17932_LivreCW8Abstract.pdf

  • Azam P, Peiffer J-L, Chamousset D, Tissier M-H, Bonnet P-A, Vian L, Fabre I, Ourlin J-C (2006) The cytokine-dependent MUTZ-3 cell line as an in vitro model for screening of contact sensitizers. Toxicol Appl Pharmacol 212:14–23

    PubMed  CAS  Google Scholar 

  • Ball N, Cagen S, Carrillo JC, Certa H, Eigler D, Emter R, Faulhammer F, Garcia C, Graham C, Haux C, Kolle SN, Kreiling R, Natsch A, Mehling A (2011) Evaluating the sensitization potential of surfactants: integrating data from the local lymph node assay, guinea pig maximization test, and in vitro methods in a weight-of-evidence approach. Regul Toxicol Pharmacol 60:389–400

    PubMed  CAS  Google Scholar 

  • Banchereau J, Steinmann RM (1998) Dendritic cells and the control of immunity. Nature 392:245–252

    PubMed  CAS  Google Scholar 

  • Barker JN (1992) Role of keratinocytes in allergic contact dermatitis. Contact Dermatitis 26:145–148

    PubMed  CAS  Google Scholar 

  • Basketter DA, Kimber I (2010) Skin sensitization, false positives and false negatives: experience with guinea pig assays. J Appl Toxicol 30:381–386

    PubMed  CAS  Google Scholar 

  • Basketter DA, Lea LJ, Cooper K, Stocks J, Dickens A, Pate I, Dearman RJ, Kimber I (1999) Threshold for classification as a skin sensitizer in the local lymph node assay. A statistical evaluation. Food Chem Toxicol 37:1167–1174

    PubMed  CAS  Google Scholar 

  • Basketter DA, Cockshott A, Corsini E, Gerberick GF, Idehara K, Kimber I, Van Loveren H, Matheson J, Mehling A, Omori T, Rovida C, Sozu T, Takeyoshi M, Casati S (2008) An evaluation of performance standards and non-radioactive endpoints for the local lymph node assay. The report and recommendations of ECVAM Workshop 65. ATLA 36:243–257

    PubMed  CAS  Google Scholar 

  • Basketter D, Kolle SN, Schrage A, Honarvar N, Gamer AO, van Ravenzwaay B, Landsiedel R (2011) Experience with local lymph node assay performance standards using radioactivity and nonradioactive cell count measurements. J Appl Toxicol. doi:10.1002/jat.1684

    PubMed  Google Scholar 

  • Bauch C, Kolle SN, Fabian E, Pachel C, Ramirez T, Wiench B, Wruck CJ, van Ravenzwaay B, Landsiedel R (2011) Intralaboratory validation of four in vitro assays for the prediction of the skin sensitizing potential of chemicals. Toxicol In Vitro 25:1162–1168

    PubMed  CAS  Google Scholar 

  • Bauch C, Kolle SN, Ramirez T, Eltze T, Fabian E, Mehling A, Teubner W, van Ravenzwaay B, Landsiedel R (2012) Putting the parts together: combining in vitro methods to test for skin sensitizing potentials. Regul Toxicol Pharmacol (in revision)

  • Bauer B, Andersson SI, Stenfeldt AL, Simonsson C, Bergstroom J, Ericson MB, Jonsson CA, Broo KS (2011) Modification and expulsion of keratins by human epidermal keratinocytes upon hapten exposure in vitro. Chem Res Toxicol 24:737–743

    PubMed  CAS  Google Scholar 

  • Bechetoille N, Vachon H, Gaydon A, Boher A, Fontaine T, Schaffer E, André-Frei V, Mueller CG (2011) A new organotypic model containing dermal-type macrophages. Exp Dermatol 20:1035–1037

    PubMed  CAS  Google Scholar 

  • Becker D, Valk E, Zahn S, Brand P, Knop J (2003) Coupling of contact sensitizers to thiol groups is the key event for the activation of monocytes and monocyte-derived dendritic cells. J Invest Dermatol 120:233–238

    PubMed  CAS  Google Scholar 

  • Buehler EV (1965) Delayed contact hypersensitivity in the guinea pig. Arch Dermatol 91:171–177

    PubMed  CAS  Google Scholar 

  • Cao YP, Ma PC, Liu WD, Zhou WQ, Tao Y, Zhang ML, Li LJ, Chen ZY (2011) Evaluation of the skin sensitization potential of chemicals in THP-1/keratinocyte co-cultures. Immunopharmacol Immunotoxicol 34:196–204

    PubMed  Google Scholar 

  • Casati S, Aeby P, Basketter DA, Cavani A, Gennari A, Gerberick GF, Griem P, Hartung T, Kimber I, Lepoittevin J-P, Meade BJ, Pallardy M, Rougier N, Rousset F, Rubinstenn G, Sallusto F, Verheyen GR, Zuang V (2005) Dendritic cells as a tool for the predictive identification of skin sensitization hazard. Altern Lab Anim 33:47–62

    PubMed  CAS  Google Scholar 

  • Caux C, Vanbervliet B, Massacrier C, Dezutter-Dambuyant C, de Saint-Vis B, Jacquet C, Yoneda K, Imamura S, Schmitt D, Banchereau J (1997) CD34 + hemapoetic progenitors from human cord blood differentiate along two independent dendritic cell pathways in response to GM-CSF + TNF alpha. J Exp Med 184:695–706

    Google Scholar 

  • Chaudhry Q, Piclin N, Cotterill J, Pintore M, Price NR, Chrétien JR, Roncaglioni A (2010) Global QSAR models of skin sensitizers for regulatory purposes. Chem Cent J 29(4 Suppl 1):S5

    Google Scholar 

  • Corsini E, Marinovich M, Galli CL (1995) In vitro keratinocytes responses to chemical allergens. Boll Chim Farm 134:569–573

    PubMed  CAS  Google Scholar 

  • Corsini E, Mitjans M, Galbiati V, Lucchi L, Galli CL, Marinovich M (2009) Use of IL-18 production in human keratinocyte cell line to discriminate contact sensitizers from irritants and low molecular weight respiratory allergens. Toxicol In Vitro 23:789–796

    PubMed  CAS  Google Scholar 

  • Cottrez F, Auriault C, Groux H (2011) Development of IRR-IS®, an Episkin® based model for quantifying chemical irritation potency using an algorithm based on analysis of magnitude of gene expression of selected biomarkers. 8th World congress on alternatives & animal use in the life sciences, Montreal; ALTEX 28, Special Issue, Montreal 2011 http://www.wc8.ccac.ca/files/C17932_LivreCW8Abstract.pdf

  • Cumberbatch M, Dearman RJ, Kimber I (1996) Constitutive and inducible expression of interleukin-6 by Langerhans cells and lymph node dendritic cells. Immunology 87:513–518

    PubMed  CAS  Google Scholar 

  • Cumberbatch M, Dearman RJ, Antopoulos C, Groves RW, Kimber I (2001) Interleukin-18 induces Langerhans cell migration by tumor necrosis factor-a and IL-1b-dependent mechanism. Immunology 102:323–330

    PubMed  CAS  Google Scholar 

  • Dai R, Streilein JW (1998) Naïve hapten-specific human T-lymphocytes are primed in vitro with derivatized blood mononuclear cells. J Invest Dermatol 110:29–33

    PubMed  CAS  Google Scholar 

  • De Smedt ACA, Van den Heuvel RL, Van Tendeloo VFI, Berneman ZN, Schoeters GER (2005) Capacity of CD34 + progenitor-derived dendritic cells to distinguish between sensitizers and irritants. Toxicol Lett 156:377–398

    PubMed  Google Scholar 

  • De Wever B, Fuchs HW, Gaca M, Krul C, Mikulowski S, Poth A, Roggen EL, Vilà MR (2012) Implementation challenges for designing integrated in vitro testing strategies (ITS) aiming at reducing and replacing animal experimentation. Toxicol In Vitro 26:526–534

    PubMed  Google Scholar 

  • Dietz L, Esser PR, Schmucker SS, Goette I, Richter A, Schnotzer M, Martin SF, Thierse HJ (2010) Tracking human contact allergens: from mass spectrometric identification of peptide-bound reactive small chemicals to chemical-specific naïve human T-cell priming. Toxicol Sci 117:236–247

    Google Scholar 

  • Dimitrov SD, Low LK, Patlewicz GY, Kern PS, Dimitrova GD, Comber MHI, Philips RD, Niemela J, Bailey PT, Mekenyan OG (2005) Skin sensitization: modeling based on skin metabolism simulation and formation of protein conjugates. Int J Toxicol 24:89–204

    Google Scholar 

  • Dos Santos GG, Reinders J, Ouwehand K, Rustemeyer T, Scheper RJ, Gibbs S (2009) Progress on the development of human in vitro cell based assays for assessment of the sensitizing potential of compounds. Toxicol Appl Pharmacol 236:372–382

    PubMed  Google Scholar 

  • Dos Santos GG, Spiekstra SW, Sampat-Sardjoepersad SC, Reinders J, Scheper RJ, Gibbs S (2011) A potential in vitro epidermal equivalent assay to determine sensitizer potency. Toxicol In Vitro 25:347–357

    PubMed  Google Scholar 

  • Dupuis G, Benezra C (1982) Allergic contact dermatitis to simple chemicals: a molecular approach. Marcel Dekker Inc., New York

    Google Scholar 

  • EC 1907/2006. Regulation (EC) No 1907/2006 of the European Parliament and the council of 18 December 2006 concerning the Registration, Evaluation, Authorisation and Restriction of chemicals (REACH), establishing a European Chemicals Agency, amending Directive 1999/45/EC and repealing Council Regulation (EEC) No 793/93 and Commission Regulation (EC) No 1488/94 as well as Council Directive 76/769/EEC and Commission Directives 91/155/EEC, 93/67/EEC, 93/105/EC and 2000/21/EC

  • Ehling G, Hecht M, Heusener A, Huesler J, Gamer AO, van Loveren H, Maurer T, Riecke K, Ullmann L, Ulrich P, Vandebriel R, Vohr HW (2005) An European interlaboratory validation of alternative endpoints of the murine local lymph node assay: first round. Toxicology 212:60–68

    PubMed  CAS  Google Scholar 

  • Emter R, Ellis G, Natsch A (2010) Performance of a novel keratinocyte-based reporter cell line to screen skin sensitizers in vitro. Toxicol Appl Pharmacol 245:281–290

    PubMed  CAS  Google Scholar 

  • Enk AH, Katz SI (1992) Early molecular events in the induction phase of contact sensitivity. Proc Nat Acad Sci USA 89:1398–1402

    PubMed  CAS  Google Scholar 

  • Galbiati V, Mitjans M, Lucchi L, Viviani B, Galli CL, Marinovich M, Corsini E (2011) Further development of the NCTC 2544 IL-18 assay to identify in vitro contact allergens. Toxicol In Vitro 25:724–732

    PubMed  CAS  Google Scholar 

  • Gerberick GF, Vassallo JD, Bailey RE, Chaney JG, Morrall SW, Lepoittevin JP (2004) Development of peptide reactivity assay for screening contact allergens. Toxicol Sci 81:332–343

    PubMed  CAS  Google Scholar 

  • Gerberick GF, Vassallo JD, Foertsch LM, Price BB, Chaney JG, Lepoittevin J-P (2007) Quantification of chemical peptide reactivity for screening contact allergens: a classification tree model approach. Toxicol Sci 97:417–427

    PubMed  CAS  Google Scholar 

  • Gerberick GF, Troutman JA, Foertsch LM, Vassallo JD, Quijano M, Dobson RLM, Goebel C, Lepoittevin J-P (2009) Investigation of peptide reactivity of pro-hapten sensitizers using a peroxidase–peroxidase oxidation system. Toxicol Sci 112:164–174

    PubMed  CAS  Google Scholar 

  • Gildea LA, Ryan CA, Foertsch LM, Kennedy JM, Dearman RJ, Kimber I, Gerberick GF (2006) Identification of gene expression changes induced by chemical allergens in dendritic cells: opportunities for skin sensitization testing. J Invest Dermatol 126:1813–1822

    PubMed  CAS  Google Scholar 

  • Guironnet G, Dalbriez-Gauthier C, Rousset F, Schmitt D, Peguet-Navarro J (2000) In vitro human T-cell sensitization to haptens by monocyte-derived dendritic cells. Toxicol In Vitro 14:517–522

    PubMed  CAS  Google Scholar 

  • Han EH, Hwang YP, Jeong TC, Lee SS, Shin JG, Jeong HG (2007) Eugenol inhibit 7,12-dimethylbenz(a)anthracene-induced gentoxicity in MCF-7 cells: bifunctional effects on CYP1 and NAD(P)H:quinine oxidoreductase. FEBS Lett 581:749–756

    PubMed  CAS  Google Scholar 

  • Hanau D, Schmitt DA, Fabre M, Cazenave JP (1988) A method for the rapid isolation of human epidermal Langerhans cells using immunomagnetic microspheres. J Invest Dermatol 91:274–279

    PubMed  CAS  Google Scholar 

  • Haneke KE, Tice RR, Carson BL, Margolin BH, Stokes WS (2001) ICCVAM evaluation of the murine local lymph node assay. Data analyses completed by the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods (2001). Regul Toxicol Pharmacol 34:274–286

    PubMed  CAS  Google Scholar 

  • Hartung T (2009) A toxicology for the 21st century- mapping the road ahead. Toxicol Sci 109:18–23

    PubMed  CAS  Google Scholar 

  • Hartung T, Blaauboer BJ, Bosgra S, Carney E, Coenen J, Conolly RB, Corsini E, Faustman EM, Gaspari A, Hayashi M, Hayes AW, Hengstler JG, Knudsen LE, Knudsen TB, McKim JM, Pfaller W, Roggen EL (2011) An expert consortium review of the EC-commissioned report “alternative (non-animal) methods for cosmetic testing: current status and future prospects -2010”. ALTEX 28:183–209

    PubMed  Google Scholar 

  • Hennen J, Aeby P, Goebel C, Schettgen T, Oberli A, Kalmes M, Blömeke B (2011) Cross talk between keratinocytes and dendritic cells: impact on the prediction of sensitization. Toxicol Sci 123:501–510

    PubMed  CAS  Google Scholar 

  • Hooyberghs J, Schoeters E, Lambrechts N, Nelissen I, Witters H, Schoeters G, Van Den Heuvel R (2008) A cell-based in vitro alternative to identify skin sensitizers by gene expression. Toxicol Appl Pharmacol 231:103–111

    PubMed  CAS  Google Scholar 

  • Hulette BC, Ryan CA, Gildea LA, Gerberick GF (2002) Elucidating changes in surface marker expression of dendritic cells following chemical allergen treatment. Toxicol Appl Pharmacol 182:226–233

    PubMed  CAS  Google Scholar 

  • Hulette BC, Ryan A, Gildea LA, Gerberick GF (2005) Relationship of CD86 surface marker expression and cytotoxicity on dendritic cells exposed to chemical allergen. Toxicol Appl Pharmacol 209:159–166

    PubMed  CAS  Google Scholar 

  • Inaba K, Inaba M, Romani N, Aya H, Deguchi M, Ikehara S, Muramatsu S, Steinman RM (1992) Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony stimulating factor. J Exp Med 176:1693–1702

    PubMed  CAS  Google Scholar 

  • Jacobs JJL, Lehe CL, Hasegawa H, Elliott GR, Das PK (2006) Skin irritants and contact sensitizers induce Langerhans cell migration and maturation at an irritant concentration. Exp Dermatol 15:432–440

    PubMed  CAS  Google Scholar 

  • Jaworska J, Harol A, Kern PS, Gerberick GF (2011) Integrating non-animal test information into an adaptive testing strategy- skin sensitization proof of concept case. ALTEX 28:211–225

    PubMed  Google Scholar 

  • Johansson H, Lindstedt M, Albrekt A-S, Borrebaeck CAK (2011) A genomic biomarker signature can predict skin sensitizers using a cell-based in vitro alternative to animal tests. BMC Genomics 12:399

    PubMed  CAS  Google Scholar 

  • Jowsey IR, Basketter DA, Westmoreland C, Kimber I (2006) A future approach to measuring relative skin sensitization: a proposal. J Appl Toxicol 26:341–350

    PubMed  CAS  Google Scholar 

  • Kim BS, Miyagawa F, Cho Y-H, Bennett CL, Clausen BE, Katz SI (2009) Keratinocytes function as accessory cells for presentation of endogenous antigen expressed in the epidermis. J Invest Dermatol 129:2805–2817

    PubMed  CAS  Google Scholar 

  • Kimber I, Basketter DA (1992) The murine local lymph node assay: a commentary on collaborative studies and new directions. Food Chem Toxicol 2:165–169

    Google Scholar 

  • Kimber I, Dearman RJ (2002) Allergenic contact dermatitis: the cellular effectors. Contact Dermatitis 46:1–5

    PubMed  Google Scholar 

  • Kimber I, Basketter DA, Butler M, Gamer A, Garrigue J-L, Gerberick GF, Newsome C, Steiling W, Vohr W-H (2003) Classification of contact allergens according to potency: proposals. Food Chem Toxicol 41:1799–1809

    PubMed  CAS  Google Scholar 

  • Kimber I, Basketter DA, Gerberick FG, Ryan CA, Dearman RJ (2011) Chemical allergy: translating biology into chemical characterisation. Toxicol Sci 120:S238–S268

    PubMed  CAS  Google Scholar 

  • Kligman AM (1966) The identification of contact allergens by human assay. 3. The maximization test: a procedure for screening and rating contact sensitizers. J Invest Dermatol 47:393–409

    PubMed  CAS  Google Scholar 

  • Koeper LM, Schulz A, Ahr HJ, Vohr HW (2007) In vitro differentiation of skin sensitizers by cell signaling pathways. Toxicology 242:144–152

    PubMed  CAS  Google Scholar 

  • Kojima H, Takeyoshi M, Sozu T, Awagi T, Arima K, Idehara K, Ikarashi Y, Kanazawa Y, Maki E, Omori T, Yuasa A, Yoshimura I (2010) Interlaboratory validation of the modified murine local lymph node assay based on 5-bromo-2′-deoxyuridine incorporation. J Appl Toxicol 31:63–74

    Google Scholar 

  • Krasteva M, Peguet-Navarro J, Moulon C, Courtellemont P, Redziniak G, Scmitt D (1996) In vitro primary sensitization of hapten-specific T cells by cultured human epidermal Langerhans cells- a screening predictive assay for contact sensitizers. Clin Exp Allergy 26:563–570

    PubMed  CAS  Google Scholar 

  • Kreiling R, Hollnagel HM, Hareng L, Eigler D, Lee MS, Griem P, Dreessen B, Kleber M, Albrecht A, Garcia C, Wendel A (2008) Comparison of the skin sensitizing potential of unsaturated compounds as assessed by the murine local lymph node assay (LLNA) and the guinea pig maximization test (GPMT). Food Chem Toxicol 46:1896–1904

    PubMed  CAS  Google Scholar 

  • Lambrechts N, Verstraelen S, Lodewyckx H, Felicio A, Hooyberghs J, Witters H, Van Tendeloo V, Van Cauwenberge P, Nelissen I, Van der Heuvel R, Schoeters G (2009) THP-1 monocytes but not macrophages as potential alternative for CD34 + dendritic cells to identify chemical skin sensitizers. Toxicol Appl Pharmacol 236:221–230

    PubMed  CAS  Google Scholar 

  • Lambrechts N, Vanheel H, Hooyberghs J, De Boever P, Witters H, Van den Heuvel R, Van Tendeloo V, Nelissen I, Schoeters G (2010a) Gene markers in dendritic cells unravel pieces of the skin sensitization puzzle. Toxicol Lett 196:95–103

    PubMed  CAS  Google Scholar 

  • Lambrechts N, Vanheel H, Nelissen I, Witters H, Van Den Heuvel R, Van Tendeloo V, Schoeters G, Hooyberghs J (2010b) Assessment of chemical skin-sensitizing potency by an in vitro assay based on human dendritic cells. Toxicol Sci 116:122–129

    PubMed  CAS  Google Scholar 

  • Lambrechts N, Nelissen I, Van Tendeloo V, Witters H, Van den Heuvel R, Hooyberghs J, Schoeters G (2011) Functionality and specificity of gene markers for skin sensitization in dendritic cells. Toxicol Lett 203:106–110

    PubMed  CAS  Google Scholar 

  • Landsteiner K, Jacobs J (1936) Studies on the sensitization of animals with simple chemical compounds II. J Exp Med 64:625–639

    PubMed  CAS  Google Scholar 

  • Lenz A, Heine M, Schuler G, Romani N (1993) Human and murine dermis contain dendritic cells. Isolation by means of a novel method and phenotypical and functional characterization. J Clin Invest 92:2587–2596

    PubMed  CAS  Google Scholar 

  • Lepoittevin J-P (2006) Metabolism versus chemical transformation or pro-versus prehaptens? Contact Dermatitis 54:73–74

    PubMed  Google Scholar 

  • Lepoittevin J-P, Basketter DA, Goossens A, Karlberg A-T (1998) Allergic contact dermatitis: the molecular basis. Springer, Berlin

    Google Scholar 

  • Lewis JB, Messer RL, McCloud VV, Lockwood PE, Hsu SD, Wataha J (2006) Ni(II) activates the Nrf2 signaling pathway in human monocytic cells. Biomaterials 27:5348–5356

    PubMed  CAS  Google Scholar 

  • Lim Y-M, Moon S-J, A S–S, Lee S-J, Kim S-Y, Chang I-S, Park K-L, Kim H-A, Heo Y (2008) Suitability of macrophage inflammatory protein-1b production by THP-1 cells in differentiating skin sensitizers from irritants. Contact Dermatitis 58:193–198

    PubMed  CAS  Google Scholar 

  • Magnusson B, Kligman AM (1969) The identification of contact allergens by animal assay. The guinea pig maximization test. J Invest Dermatol 52:268–276

    PubMed  CAS  Google Scholar 

  • Martin SF, Esser PR, Schmucker S, Dietz L, Naisbitt DJ, Park BK, Vocanson M, Nicolas JF, Keller M, Pichler WJ, Peiser M, Luch A, Wanner R, Maggi E, Cavani A, Rustemeyer T, Richter A, Thierse HJ, Sallusto F (2010) T-cell recognition of chemicals, protein allergens and drugs: towards the development of in vitro assays. Cell Mol Life Sci 67:4171–4184

    PubMed  CAS  Google Scholar 

  • Martinozzi-Teissier S, Cottrez F, Tourneix F, Groux H, Meunier JR (2011) Evaluation of SENS-IS®, an Episkin® based model for identifying chemical sensitizers. 8th World congress on alternatives & animal use in the life sciences, Montreal; ALTEX 28, Special Issue, Montreal 2011. http://www.wc8.ccac.ca/files/C17932_LivreCW8Abstract.pdf

  • Matsue H, Cruz PD, Bergstresser PR, Takashima A (1992) Cytokine expression by epidermal cell subpopulations. J Invest Dermatol 99:42S–45S

    PubMed  CAS  Google Scholar 

  • Maxwell G, MacKay C (2008) Application of systems biology approach to skin allergy risk assessment. Altern Lab Anim 36:521–556

    PubMed  CAS  Google Scholar 

  • Maxwell G, Aeby P, Ashikaga T, Bessou-Touya S, Diembeck W, Gerberick F, Kern P, Marrec-Fairley M, Ovigne J-M, Sakaguchi H, Schroeder K, Tailhardat M, Teissier S, Winkler P (2011) Skin sensitsation: the Colipa strategy for developing and evaluating non-animal test methods for risk assessment. ALTEX 28:50–55

    PubMed  Google Scholar 

  • McKim JM, Keller DJ, Gorski JR (2010) A new in vitro method for identifying chemical sensitizers combining peptide binding with ARE/EpER-mediated gene expression in human skin cells. Cut Ocul Toxicol 29:171–192

    CAS  Google Scholar 

  • McNamee PM, Api AM, Basketter DA, Frank Gerberick G, Gilpin DA, Hall BM, Jowsey I, Robinson MK (2008) A review of critical factors in the conduct and interpretation of the human repeat insult patch test. Regul Toxicol Pharmacol 52:24–34

    PubMed  Google Scholar 

  • Mewes KR, Raus M, Bernd A, Zöller NN, Sättler A, Graf R (2007) Elastin expression in a newly developed full-thickness skin equivalent. Skin Pharmacol Physiol 20:85–95

    PubMed  CAS  Google Scholar 

  • Mitjans M, Viviani B, Lucchi L, Galli CL, Marinovich M, Corsini E (2008) Role of p38 MAPK in the selective release of IL-8 induced by chemical allergen in naïve THP-1 cells. Toxicol In Vitro 22:386–395

    PubMed  CAS  Google Scholar 

  • Mitjans MM, Galbiati V, Lucchi L, Viviani B, Marinovich M, Galli CL, Corsini E (2010) Use of IL-8 release and p38 MAPK activation in THP-1 cells to identify allergens and to assess their potency in vitro. Toxicol In Vitro 24:1803–1809

    PubMed  CAS  Google Scholar 

  • Miyazawa M, Ito Y, Yoshida Y, Sakaguchi H, Suzuki H (2007) Phenotypic alterations and cytokine production in THP-1 cells in response to allergens. Toxicol In Vitro 21:428–437

    PubMed  CAS  Google Scholar 

  • Miyazawa M, Ito Y, Kosaka N, Nukada Y, Sakaguchi H, Suzuki H, Nishiyama N (2008) Role of TNF-a and extracellular ATP in THP-1 cell activation following allergen exposure. J Toxicol Sci 33:71–83

    PubMed  CAS  Google Scholar 

  • Motohashi H, Yamamoto M (2004) Nrf2-Keap1 defines a physiologically important stress response mechanism. Trends Mol Med 10:549–557

    PubMed  CAS  Google Scholar 

  • Moulon C, Perguet-Navarro J, Courtellemont P, Redziniak G, Schmitt D (1993) In vitro primary sensitization and restimulation of hapten-specific T-cells by fresh and cultured human epidermal Langerhans cells. Immunology 80:373–379

    PubMed  CAS  Google Scholar 

  • Natsch A (2010) The Nrf2-Keap1 toxicity pathway as a cellular sensor for skin sensitizers-functional relevance and a hypothesis on innate reactions to skin sensitizers. Toxicol Sci 113:284–292

    PubMed  CAS  Google Scholar 

  • Natsch A, Emter R (2008) Skin sensitizers induce antioxidant response element dependent genes: application to the in vitro testing of the sensitization potential of chemicals. Toxicol Sci 102:110–119

    PubMed  CAS  Google Scholar 

  • Natsch A, Gfeller H (2008) LC-MS-based characterization of the peptide reactivity of chemicals to improve the in vitro prediction of the skin sensitization potential. Toxicol Sci 106:464–478

    PubMed  CAS  Google Scholar 

  • Natsch A, Gfeller H, Rothaupt M, Ellis G (2007) Utility and limitations of a peptide reactivity assay to predict fragrance allergens in vitro. Toxicol In Vitro 21:1220–1226

    PubMed  CAS  Google Scholar 

  • Natsch A, Emter R, Ellis G (2009) Filling the concept with data: integrating data from different in vitro and in silico assays on skin sensitizers to explore the battery approach for animal-free skin sensitization testing. Toxicol Sci 107:106–121

    PubMed  CAS  Google Scholar 

  • Natsch A, Bauch C, Foertsch L, Gerberick F, Norman K, Hilberer A, Inglis H, Landsiedel R, Onken S, Reuter H, Schepky A, Emter R (2011) The intra- and interlaboratory reproducibility and predictivity of the KerationoSens assay to predict skin sensitizers in vitro: results of a ring-study in five laboratories. Toxicol In Vitro 25:733–744

    Google Scholar 

  • Nguyen SH, Dang TP, MacPherson C, Maibach H, Maibach HI (2008) Prevalence of patch test results from 1970 to 2002 in a multi-centre population in North America (NACDG). Contact Dermatitis 58:101–106

    PubMed  Google Scholar 

  • Nukada Y, Miazazawa M, Kosaka N, Ito Y, Sakaguchi H, Nishiyama N (2008) Production of IL-8 in THP-1 cells following contact allergen stimulation via mitogen-activated protein kinase activation or tumor necrosis factor-a production. J Tox Sci 33:175–185

    CAS  Google Scholar 

  • Nukada Y, Ito Y, Miyazawa M, Sakaguchi H, Nishiyama N (2011a) The relationship between CD86 and CD54 protein expression and cytotoxicity following stimulation with contact allergen in THP-1 cells. J Toxicol Sci 36:313–324

    PubMed  CAS  Google Scholar 

  • Nukada Y, Ashikaga T, Sakaguchi H, Sono S, Mugita N, Hirota M, Miyazawa M, Ito Y, Sasa H, Nishiyama N (2011b) Predictive performance for human skin sensitizing potential of the human cell line activation test (h-CLAT). Contact Dermatitis 65:343–353

    PubMed  CAS  Google Scholar 

  • OECD Guideline for the testing of chemicals 406: Skin Sensitization, adopted: 17 July 1992. http://www.oecd-ilibrary.org/environment/oecd-guidelines-for-the-testing-of-chemicals-section-4-health-effects_20745788

  • OECD Guideline for the testing of chemicals 429: Skin Sensitization: Local Lymph Node Assay revised 2010 http://www.oecd-ilibrary.org/environment/oecd-guidelines-for-the-testing-of-chemicals-section-4-health-effects_20745788

  • OECD: The Adverse Outcome Pathway for Skin Sensitisation Initiated by Covalent Binding to Proteins (2012) OECD ENVIRONMENT, HEALTH AND SAFETY PUBLICATIONS: No.168; ENV/JM/MONO(2012)10

  • Okamura H, Tsutsi H, Komatsu T, Yutsudo M, Hakura A, Tanimoto T, Torigoe K, Okura T, Nukada Y, Hattori K et al (1995) Cloning of a new cytokine that induces IFN-g production by T-cells. Nature 378:88–91

    PubMed  CAS  Google Scholar 

  • Ouwehand K, Spiekstra SW, Reinders J, Scheper RJ, de Gruijl TD, Gibbs S (2010) Comparison of a novel CXCL12/CCL5 dependent migration assay with CXCL8 secretion and CD86 expression for distinguishing sensitizers from non-sensitizers using MUTZ-3 Langerhans cells. Toxicol In Vitro 24:578–585

    PubMed  CAS  Google Scholar 

  • Ozawa H, Nakagawa S, Tagami H, Aiba S (1996) Interleukin-1b and granulocyte macrophage colony-stimulating factor mediate Langerhans cell maturation differently. J Invest Dermatol 106:441–445

    PubMed  CAS  Google Scholar 

  • Peiser M, Tralau T, Heidler J, Api AM, Arts JHE, Basketter DA, English J, Diepgen TL, Fuhlbrigge RC, Gaspari AA, Johansen JD, Karlberg AT, Kimber I, Lepoittevin JP, Liebsch M, Maibach HI, Martin SF, Merk HF, Platzek T, Rustemeyer T, Schnuch A, Vandebriel RJ, White IR, Luch A (2012) Allergic contact dermatitis: epidemiology, molecular mechanisms, in vitro methods and regulatory aspects. Cell Mol Life Sci 69:763–781

    PubMed  CAS  Google Scholar 

  • Pendlington RU, Minter HJ, Stupart L, MacKay C, Roper CS, Sanders DJ, Pease CK (2008) Development of a modified in vitro skin absorption method to study the epidermal/dermal disposition of contact allergen in human skin. Cutan Ocul Toxicol 27:283–294

    PubMed  CAS  Google Scholar 

  • Python F, Goebel C, Aeby P (2007) Assessment of the U937 cell line for the detection of contact allergens. Toxicol Appl Pharmacol 220:113–124

    PubMed  CAS  Google Scholar 

  • Python F, Goebel C, Aeby P (2009) Comparative DNA microarray analysis of human monocyte derived dendritic cells and MUTZ-3 cells exposed to the moderate skin sensitizer cinnamaldehyde. Toxicol Appl Pharmacol 239:273–283

    PubMed  CAS  Google Scholar 

  • Rees B, Spiekstra SW, Carfi M, Ouwehand K, Williams CA, Corsini E, McLeod JD, Gibbs S (2011) Interlaboratory study of the in vitro dendritic cell migration assay for identification of contact allergens. Toxicol In Vitro 25:2124–2134

    PubMed  CAS  Google Scholar 

  • Reuter H, Spieker J, Gerlach S, Engels U, Pape W, Kolbe L, Schmucker R, Wenck H, Diembeck W, Wittern K-P, Reisinger K, Schepky AG (2011) In vitro detection of contact allergens: development of an optimized protocol using human peripheral blood monocyte-derived dendritic cells. Toxicol In Vitro 25:315–323

    PubMed  CAS  Google Scholar 

  • Rougier N, Redziniak G, Mougin D, Schmitt D, Vincent C (2000) In vitro evaluation of the sensitization potential of weak contact allergens using Langerhans cell-like dendritic cells and autologous T cells. Toxicology 145:73–82

    PubMed  CAS  Google Scholar 

  • Rovida C (2011) Local lymph node assay: how testing laboratories apply OECD TG 429 for REACH purposes. ALTEX 28:117–129

    PubMed  Google Scholar 

  • Russell WMS, Burch RL (1959) The principles of humane experimental technique. Methuen, Co. Ltd., London

    Google Scholar 

  • Rustemeyer T, De Ligter S, von Blomberg BM, Frosch PJ, Scheper RJ (1999) Human T lymphocyte priming in vitro by haptenated autologous dendritic cells. Clin Exp Immunol 117:209–216

    PubMed  CAS  Google Scholar 

  • Ryan CA, Gildea LA, Hulette BC, Dearman RJ, Kimber I, Gerberick GF (2004) Gene expression changes in peripheral blood derived dendritic cells following exposure to a contact allergen. Toxicol Lett 150:301–316

    PubMed  CAS  Google Scholar 

  • Sakaguchi H, Ashikaga T, Miyazawa M, Yoshida Y, Ito Y, Yoneyama K, Hirota M, Itagaki H, Tyoda H, Suzuki H (2006) Development of an in vitro skin sensitization test using human cell lines: human cell line activation test (h-CLAT) II. An interlaboratory study of the h-CLAT. Toxicol In Vitro 20:774–784

    PubMed  CAS  Google Scholar 

  • Sakaguchi H, Ashikaga T, Miyazawa M, Kosaka N, Ito Y, Yoneyama K, Sono S, Itagaki H, Toyoda H, Suzuki H (2009) The relationship between CD86/CD54 expression and THP-1 cell viability in an in vitro skin sensitization test- human cell line activation test (h-CLAT). Cell Biol Toxicol 25:109–126

    PubMed  CAS  Google Scholar 

  • Sakaguchi H, Ryan C, Ovigne J-M, Scroeder KR, Ashikaga T (2010) Predicting skin sensitization potential and interlaboratory reproducibility of a human cell line activation test (h-CLAT) in the European Cosmetics Association (COLPIA) ring trials. Toxicol In Vitro 24:1810–1820

    PubMed  CAS  Google Scholar 

  • Sallusto F, Lanzavecchia A (1994) Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and down-regulated by tumor necrosis factor alpha. J Exp Med 179:1109–1118

    PubMed  CAS  Google Scholar 

  • Schäfer-Korting M, Bock U, Diembeck W, Düsing HJ, Gamer A, Haltner-Ukomadu E, Hoffmann C, Kaca M, Kamp H, Kersen S, Kietzmann M, Korting HC, Krächter HU, Lehr CM, Liebsch M, Mehling A, Müller-Goymann C, Netzlaff F, Niedorf F, Rübbelke MK, Schäfer U, Schmidt E, Schreiber S, Spielmann H, Vuia A, Weimer M (2008) The use of reconstructed human epidermis for skin absorption testing: results of the validation study. Altern Lab Anim 36:161–187

    PubMed  Google Scholar 

  • Schoeters E, Verheyen GR, van den Heuvel R, Nelissen I, Witters H, van Tendeloo VFI, Schoeters GER, Berneman ZN (2005) Expression analysis of immune-related genes in CD34 + progenitor-derived dendritic cells after exposure to the chemical contact allergen DNCB. Toxicol In Vitro 19:909–913

    PubMed  CAS  Google Scholar 

  • Schoeters E, Nuijten J-M, van der Heuvel RL, Nelissen I, Witters H, Schoeters GER, van Tendeloo VFI, Barneman ZN, Verheyen GR (2006) Gene expression signatures in CD34 + -progenitor derived dendritic cells exposed to the chemical contact allergen nickel sulfate. Toxicol Appl Pharmacol 216:131–149

    PubMed  CAS  Google Scholar 

  • Schoeters E, Verheyen GR, Nelissen I, Van Rompay AR, Hooyberghs J, Van der Heuvel RL, Witters H, Shoeters GER, Van Tendeloo VFI, Berneman ZN (2007) Microarray analyses in dendritic cells reveal potential biomarkers for chemical-induced skin sensitization. Mol Immunol 44:3222–3233

    PubMed  CAS  Google Scholar 

  • Schreiber S, Mahmoud A, Vuia A, Rübbelke MK, Schmidt E, Schaller M, Kandárová H, Haberland A, Schäfer UF, Bock U, Korting HC, Liebsch M, Schäfer-Korting M (2005) Reconstructed epidermis versus human and animal skin in skin absorption studies. Toxicol In Vitro 19:813–822

    PubMed  CAS  Google Scholar 

  • Schreiner M, Peiser M, Briechle D, Stahlmann R, Zuberbier T, Wanner R (2007) A loose-fit coculture of activated keratinocytes and dendritic cell-related cells for prediction of sensitizing potential. Allergy 62:1419–1428

    PubMed  CAS  Google Scholar 

  • Schreiner M, Peiser M, Briechle D, Stahlmann R, Zuberbier T, Wanner R (2008) A new dendritic cell type suitable as sentinel of contact allergens. Toxicology 249:146–152

    PubMed  CAS  Google Scholar 

  • Smith CM, Hotchkiss SAM (2001) Allergic contact dermatitis and metabolic mechanisms. Taylor and Francis, London

    Google Scholar 

  • Sonnenburg A, Ahuja V, Schreiner M, Platzek T, Stahlmann R (2012) Assessment of the sensitizing potential of textile disperse dyes and some of their metabolites by the loose-fit coculture-based sensitization assay (LCSA). Arch Toxicol 86:733–740

    PubMed  CAS  Google Scholar 

  • Takahashi T, Kimura Y, Saito R, Nakajima Y, Ohmiya Y, Yamasaki K, Aiba S (2011) An in vitro test to screen skin sensitizers using stable THP-1 derived IL-8 reporter cell line, THP-G8. Toxicol Sci 124:359–369

    PubMed  CAS  Google Scholar 

  • Taylor K, Casalegno C, Stengel W (2011) A critique of the EC’s expert draft reports on the status of alternatives for cosmetic testing to meet the 2013 deadline. ALTEX 28:131–148

    PubMed  Google Scholar 

  • Teunis M, Corsini E, Smits M, Madsen Bernhard C, Eltze T, Ezendam J, Galbiati V, Gremmer E, Krul C, Landin A, Landsiedel R, Pieters R, Reinders J, Roggen E, Spiekstra S, Gibbs S (2012) 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. Toxicol In Vitro (submitted)

  • Teunissen MB, Wormmeester J, Kaspenberg ML, Bos JD (1988) Enrichment of unlabeled human Langerhans cells from epidermal cell suspensions by discontinuous density gradient centrifugation. J Invest Dermatol 91:358–362

    PubMed  CAS  Google Scholar 

  • Thyssen JP, Linneberg A, Menné T, Johansen JD (2007) The epidemiology of contact allergy in the general population-prevalence and main findings. Contact Dermatitis 43:287–299

    Google Scholar 

  • Toebak MJ, Pohlmann PR, Sampat-Sardjoepersad SC, von Blomberg BM, Bruynzeel DP, Scheper RJ, Rustemeyer T, Gibbs S (2006) CXCL8 secretion by dendritic cells predicts contact allergens from irritants. Toxicol In Vitro 20:117–124

    PubMed  CAS  Google Scholar 

  • Trompezinski S, Migdal C, Tailhardat M, Le varlet B, Courtellemont P, Haftek M, Serres M (2008) Characterization of early events involved in human dendritic cell maturation induced by sensitizers: cross talk between MAPK signaling pathways. Toxicol Appl Pharmacol 230:397–406

    PubMed  CAS  Google Scholar 

  • Troutman JA, Foertsch LM, Kern PS, Dai HJ, Quijano M, Dobson RL, Lalko JF, Lepoittevin JP, Gerberick GF (2011) The incorporation of lysine into the peroxidase peptide reactivity assay for skin sensitization assessments. Toxicol Sci 122:422–436

    PubMed  CAS  Google Scholar 

  • Uchino T, Takezawa T, Ikarashi Y (2009) Reconstruction of three-dimensional human skin model composed of dendritic cells, keratinocytes and fibroblasts utilizing a handy scaffold of collagen vitrigel membrane. Toxicol In Vitro 23:333–337

    PubMed  CAS  Google Scholar 

  • Uter W, Balzer C, Geier J, Frosch PJ, Schnuch A (2005) Patch testing with patients’ own cosmetics and toiletries—results of the IVDK*, 1998–2002. Contact Dermatitis 53:226–233

    PubMed  Google Scholar 

  • van der Veen JW, Vandebriel RJ, van Loveren H, Ezendam J (2011) Keratinocytes, innate immunity and allergic contact dermatitis—opportunities for the development of in vitro assays to predict the sensitizing potential of chemicals, contact dermatitis, Dr. Young Suck Ro (Ed.), ISBN: 978-953-307-577-8, InTech, Available from: http://www.intechopen.com/books/contact-dermatitis/keratinocytes-innate-immunity-and-allergic-contact-dermatitis-opportunities-for-the-development-of-i

  • Van Och FM, Van Loveren H, Van Wolfswinkel JC, Machielsen AJ, Vandebriel RJ (2005) Assessment of potency of allergenic activity to low molecular weight compounds based on IL-1-alpha and IL-18 production by murine and human keratinocyte cell line. Toxicology 210:95–109

    PubMed  Google Scholar 

  • Vandebriel RJ, van Loveren H (2010) Non-animal sensitization testing: state of the art. Crit Rev Toxicol 40:389–404

    PubMed  CAS  Google Scholar 

  • Vandebriel RJ, Van Och FM, van Loveren H (2005) In vitro assessment of sensitizing activity of low molecular weight compounds. Toxicol Appl Pharmacol 207:142–148

    PubMed  Google Scholar 

  • Vandebriel RJ, Pennings JL, Baken KA, Pronk TE, Boorsma A, Gottschalk R, Van Loveren H (2010) Keratinocyte gene expression profiles discriminate sensitizing and irritating compounds. Toxicol Sci 117:81–89

    PubMed  CAS  Google Scholar 

  • Verheyen GR, Schoeters E, Nuijten J-M, Van den Heuvel RL, Nelissen I, Witters H, Van Tendeloo VFI, Berneman ZN, Shoeters GER (2005) Cytokine transcripts profiling in CD34 + -progenitor derived dendritic cells exposed to contact allergens and irritants. Toxicol Lett 155:187–194

    PubMed  CAS  Google Scholar 

  • Verrier AC, Schmitt D, Staquet MJ (1999) Fragrance and contact allergens in vitro modulate the HLA-DR and E-cadherin expression on human epidermal Langerhans cells. Int Arch Allergy Immunol 120:56–62

    PubMed  CAS  Google Scholar 

  • Verstraelen S, Wens B, Hooyberghs J, Nelissen I, Witters H, Schoeters G, van Cauwenberge P, Van Den Heuvel R (2008) Gene expression profiling of in vitro cultured macrophages after exposure to the respiratory sensitizer hexamethylene diisocyanate. Toxicol In Vitro 22:1107–1114

    PubMed  CAS  Google Scholar 

  • Verstraelen S, Nelissen I, Hooyberghs J, Witters H, Schoeters G, Van Cauwenberge, Van Den Heuvel R (2009a) Gene profiles of human alveolar epithelial cell line after in vitro exposure to respiratory (non-) sensitizing chemicals: identification of discriminating genetic markers and pathway analysis. Toxicol Lett 185:16–22

    PubMed  CAS  Google Scholar 

  • Verstraelen S, Nelissen I, Hooyberghs J, Witters H, Schoeters G, Van Cauwenberge P, Van Den Heuvel R (2009b) Gene profiles of THP-1 macrophages after in vitro exposure to respiratory (non-) sensitizing chemicals: identification of discriminating genetic markers and pathway analysis. Toxicol In Vitro 23:1151–1162

    PubMed  CAS  Google Scholar 

  • Yoshida Y, Sakaguchi H, Ito Y, Okuda M, Suzuki H (2003) Evaluation of the skin sensitization potential of chemicals using expression of co-stimulatory molecules CD54 and CD86, on the naïve THP-1 cell line. Toxicol In Vitro 17:221–228

    PubMed  CAS  Google Scholar 

  • Zhao Y, Balato A, Fishelevich R, Chapoval A, Mann DL, Gaspari AA (2009) Th17/Tc17 infiltration and associated cytokine gene expression in elicitation phase of allergic contact dermatitis. Br J Dermatol 161:1301–1306

    PubMed  CAS  Google Scholar 

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Acknowledgments

The authors wish to thank Dr. Ursula G. Sauer for her valuable proofreading of the manuscript and Ms. Meyasse Bugay for carefully editing the manuscript. Parts of this manuscript were used for the German BMBF project (Förderkennzeichen 0315489C).

Conflict of interest

The authors were involved in the development of several in vitro assays; they declare that they have no conflict of interest.

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Authors and Affiliations

  1. BASF Personal Care and Nutrition GmbH, Düsseldorf, Germany

    Annette Mehling

  2. Sten stures väg 69, 131 47, Nacka, Sweden

    Tove Eriksson

  3. BASF SE, Experimental Toxicology and Ecology, GV/TB, Z470, 67056, Ludwigshafen, Germany

    Tobias Eltze, Susanne Kolle, Tzutzuy Ramirez, Bennard van Ravenzwaay & Robert Landsiedel

  4. BASF Schweiz AG, Basel, Switzerland

    Wera Teubner

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Mehling, A., Eriksson, T., Eltze, T. et al. Non-animal test methods for predicting skin sensitization potentials. Arch Toxicol 86, 1273–1295 (2012). https://doi.org/10.1007/s00204-012-0867-6

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