The GARD™skin assay: Investigation of the applicability domain for metals
Article Sidebar
Main Article Content
Abstract
New approach methodologies (NAMs) for hazard identification of skin sensitizing chemicals were adopted as test guidelines by the OECD during the last decade. These alternatives to animal models align to individual key events (KE) in the adverse outcome pathway (AOP) for skin sensitization for which the molecular initiating event (MIE) is covalent binding to proteins. As it currently stands, the AOP does not include mechanistic events of sensitization by metals, and limited information is available on whether NAMs accurately predict the sensitization potential of such molecules, which have been proposed to act via alternative mechanisms to organic chemicals. Methods for assessing the sensitization potential of metals would be valuable tools to support risk management within, e.g., occupational settings during production of new metal salts or within the medical device industry to evaluate leachables from metal alloys. This paper describes a systematic evaluation of the applicability domain of the GARD™skin assay for the assessment of metals. Hazard classifications were supplemented with an extended analysis of gene expression profiles induced by metal sensitizers to compare the induction of toxicity pathways between metals and organic sensitizers. Based on the results of this study, the accuracy, sensitivity, and specificity of GARD™skin for the prediction of skin sensitizing hazard were 92% (12/13), 100% (7/7), and 83% (5/6), respectively. Thus, the performance of GARD™skin for the assessment of metals was found to be similar to that observed for conventional organic substances, providing support for inclusion of metals within the applicability domain of the test method.
Article Details
This work is licensed under a Creative Commons Attribution 4.0 International License.
Articles are distributed under the terms of the Creative Commons Attribution 4.0 International license (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the original work is appropriately cited (CC-BY). Copyright on any article in ALTEX is retained by the author(s).
Basketter, D. A. and Scholes, E. W. (1992). Comparison of the local lymph node assay with the guinea-pig maximization test for the detection of a range of contact allergens. Food Chem Toxicol 30, 65-69. doi:10.1016/0278-6915(92)90138-b
Basketter, D. A., Lea, L. J., Cooper, K. J. et al. (1999). Identification of metal allergens in the local lymph node assay. Am J Contact Dermat 10, 207-212. doi:10.1053/ajcd01000207
Basketter, D. A., Alépée, N., Ashikaga, T. et al. (2014). Categorization of chemicals according to their relative human skin sensitizing potency. Dermatitis 25, 11-21. doi:10.1097/der.0000000000000003
Bauch, C., Kolle, S. N., Ramirez, T. et al. (2012). Putting the parts together: Combining in vitro methods to test for skin sensitizing potentials. Regul Toxicol Pharmacol 63, 489-504. doi:10.1016/j.yrtph.2012.05.013
Bergal, M., Puginier, M., Gerbeix, C. et al. (2020). In vitro testing strategy for assessing the skin sensitizing potential of “difficult to test” cosmetic ingredients. Toxicol In Vitro 65, 104781. doi:10.1016/j.tiv.2020.104781
Casati, S., Griesinger, C. and Whelan, M. (2013). EURL ECVAM Recommendation on the Direct Peptide Reactivity Assay (DPRA) for Skin Sensitisation Testing. EUR 26383. Luxembourg (Luxembourg): Publications Office of the European Union. JRC85936. doi:10.2788/48229
Chipinda, I., Hettick, J. M. and Siegel, P. D. (2011). Haptenation: Chemical reactivity and protein binding. J Allergy (Cairo) 2011, 839682. doi:10.1155/2011/839682
Cleare, M. J., Hughes, E. G., Jacoby, B. et al. (1976). Immediate (type I) allergic responses to platinum compounds. Clin Allergy 6, 183-195. doi:10.1111/j.1365-2222.1976.tb01897.x
Corsini, E., Clewell, R., Cotgreave, I. et al. (2021). ESAC Opinion on the Scientific Validity of the GARDskin and GARDpotency Test Methods. Asturiol Bofill, D., Casati, S. and Viegas Barroso, J.F. (eds), Publications Office of the European Union, Luxembourg. ISBN 978-92-76-40345-6. doi:10.2760/626728
Cortes, C. and Vapnik, V. (1995). Support-vector networks. Mach Learn 20, 273-297. doi:10.1023/A:1022627411411
Daniel, A. B., Strickland, J., Allen, D. et al. (2018). International regulatory requirements for skin sensitization testing. Regul Toxicol Pharmacol 95, 52-65. doi:10.1016/j.yrtph.2018.03.003
Dearman, R. J. and Kimber, I. (2001). Cytokine fingerprinting and hazard assessment of chemical respiratory allergy. J Appl Toxicol 21, 153-163. doi:10.1002/jat.743
Dearman, R. J., Warbrick, E. V., Skinner, R. et al. (2002). Cytokine fingerprinting of chemical allergens: Species comparisons and statistical analyses. Food Chem Toxicol 40, 1881-1892. doi:10.1016/s0278-6915(02)00179-5
Dearman, R. J., Basketter, D. A. and Kimber, I. (2013). Inter-relationships between different classes of chemical allergens. J Appl Toxicol 33, 558-565. doi:10.1002/jat.1758
Dumont, C., Barroso, J., Matys, I. et al. (2016). 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. Toxicol In Vitro 34, 220-228. doi:10.1016/j.tiv.2016.04.008
ECHA – European Chemicals Agency (2010). Registration dossier Potassium permanganate. https://echa.europa.eu/de/registration-dossier/-/registered-dossier/14531/7/5/1 (accessed 13.02.2022)
ECHA (2017a). Registration dossier Palladium (II) di(4-oxopent-2-en-2-oate). https://echa.europa.eu/de/registration-dossier/-/registered-dossier/18885/1/2 (accessed 13.02.2022)
ECHA (2017b). Registration dossier Tetraammine palladium (II) hydrogen carbonate. https://echa.europa.eu/sv/registration-dossier/-/registered-dossier/19204/7/5/1 (accessed 13.02.2022)
ECHA (2017c). Registration dossier Diamminedichloropalladium. https://echa.europa.eu/de/registration-dossier/-/registered-dossier/18770/7/5/1 (accessed 13.02.2022)
ECHA (2017d). Registration dossier Hydrogen hexahydroxy platinate. https://echa.europa.eu/sv/registration-dossier/-/registered-dossier/19739/7/5/1 (accessed 13.02.2022)
ECHA (2017e). Registration dossier Tetraammine platinum (II) hydrogen carbonate. https://echa.europa.eu/sv/registration-dossier/-/registered-dossier/20065/1/2 (accessed 13.02.2022)
ECHA (2018). Registration dossier Diammonium hexachloroplatinate. https://echa.europa.eu/sv/registration-dossier/-/registered-dossier/21776/7/5/1 (accessed 13.02.2022)
ECHA (2021). OECD Test guidelines skin sensitization. https://bit.ly/3UvyOtS (accessed 01.06.2022)
Eichenbaum, G., Wilsey, J. T., Fessel, G. et al. (2021). An integrated benefit-risk assessment of cobalt-containing alloys used in medical devices: Implications for regulatory requirements in the European Union. Regul Toxicol Pharmacol 125, 105004. doi:10.1016/j.yrtph.2021.105004
EURL ECVAM – EU Reference Laboratory for Alternatives to Animal Testing (2011). 4 – Attachment2_Test Chemicals Results KeratinoSens. https://tsar.jrc.ec.europa.eu/test-method/tm2010-03
EURL ECVAM (2012). Direct Peptide Reactivity Assay (DPRA). ECVAM Validation Study Report. https://tsar.jrc.ec.europa.eu/system/files/Published/DPRA%20Validation%20Study%20Report.pdf
EURL ECVAM (2013). Human Cell Line Activation Test (h-CLAT). Validation Study Report. https://tsar.jrc.ec.europa.eu/test-method/tm2008-05
EURL ECVAM (2021). GARD™skin Assay Protocol. https://tsar.jrc.ec.europa.eu/system/files/Published/GARDskin%20Assay%20Protocol%20TSAR.pdf
Faurschou, A., Menné, T., Johansen, J. D. et al. (2011). Metal allergen of the 21st century – A review on exposure, epidemiology and clinical manifestations of palladium allergy. Contact Dermatitis 64, 185-195. doi:10.1111/j.1600-0536.2011.01878.x
Forreryd, A., Zeller, K. S., Lindberg, T. et al. (2016). From genome-wide arrays to tailor-made biomarker readout – Progress towards routine analysis of skin sensitizing chemicals with GARD. Toxicol In Vitro 37, 178-188. doi:10.1016/j.tiv.2016.09.013
Forreryd, A., Gradin, R., Humfrey, C. et al. (2023). Exploration of the GARD™skin applicability domain: Indirectly acting haptens, hydrophobic substances and UVCBs. ALTEX 40, 53-60. doi:10.14573/altex.2201281
Gibbs, S., Kosten, I., Veldhuizen, R. et al. (2018). Assessment of metal sensitizer potency with the reconstructed human epidermis IL-18 assay. Toxicology 393, 62-72. doi:10.1016/j.tox.2017.10.014
Gradin, R., Forreryd, A., Mattson, U. et al. (2021). Quantitative assessment of sensitizing potency using a dose-response adaptation of GARDskin. Sci Rep 11, 18904. doi:10.1038/s41598-021-98247-7
Hall, M. D., Telma, K. A., Chang, K. E. et al. (2014). Say no to DMSO: Dimethylsulfoxide inactivates cisplatin, carboplatin, and other platinum complexes. Cancer Res 74, 3913-3922. doi:10.1158/0008-5472.can-14-0247
Hemming, J. D. C., Hosford, M. and Shafer, M. M. (2019). Application of the direct peptide reactivity assay (DPRA) to inorganic compounds: A case study of platinum species. Toxicol Res (Camb) 8, 802-814. doi:10.1039/c9tx00242a
ICCVAM (2010). ICCVAM Test Method Evaluation Report on Using the LLNA for Testing Pesticide Formulations, Metals, Substances in Aqueous Solutions, and Other Products. N. I. o. E. H. Sciences. NIH Publication No. 10-7512. Research Triangle Park, NC: National Institute of Environmental Health Sciences.
Ikarashi, Y., Ohno, K., Tsuchiya, T. et al. (1992). Differences of draining lymph node cell proliferation among mice, rats and guinea pigs following exposure to metal allergens. Toxicology 76, 283-292. doi:10.1016/0300-483x(92)90196-l
IPA – International Platinum Group Metals Association (2017). Safe Use of Platinum Group Metals in the Workplace. https://ipa-news.de/assets/sustainability/IPA_Guidance/Chapter%201_PGM_Guide.pdf
Johansson, H., Lindstedt, M., Albrekt, A. S. et al. (2011). A genomic biomarker signature can predict skin sensitizers using a cell-based in vitro alternative to animal tests. BMC Genomics 12, 399. doi:10.1186/1471-2164-12-399
Kimber, I., Basketter, D. A., Gerberick, G. F. et al. (2011). Chemical allergy: Translating biology into hazard characterization. Toxicol Sci 120, Suppl 1, S238-268. doi:10.1093/toxsci/kfq346
Landsteiner, K. and Jacobs, J. (1936). Studies on the sensitization of animals with simple chemical compounds. J Exp Med 64, 625-639. doi:10.1084/jem.64.4.625
Makrilia, N., Syrigou, E., Kaklamanos, I. et al. (2010). Hypersensitivity reactions associated with platinum antineoplastic agents: A systematic review. Met Based Drugs 2010, 20708. doi:10.1155/2010/207084
Mandervelt, C., Clottens, F. L., Demedts, M. et al. (1997). Assessment of the sensitization potential of five metal salts in the murine local lymph node assay. Toxicology 120, 65-73. doi:10.1016/s0300-483x(97)03629-9
Martin, S. F. (2015). New concepts in cutaneous allergy. Contact Dermatitis 72, 2-10. doi:10.1111/cod.12311
Matzinger, P. (1998). An innate sense of danger. Semin Immunol 10, 399-415. doi:10.1006/smim.1998.0143
Mehling, A., Adriaens. E., Casati, S. et al. (2019). In vitro RHE skin sensitisation assays: Applicability to challenging substances. Regul Toxicol Pharmacol 108, 104473. doi:10.1016/j.yrtph.2019.104473
Natsch, A., Landsiedel, R. and Kolle, S. N. (2021). A triangular approach for the validation of new approach methods for skin sensitization. ALTEX 38, 669-677. doi:10.14573/altex.2105111
OECD (2010). Test No. 429: Skin Sensitisation: Local Lymph Node Assay. OECD Guidelines for the Testing of Chemicals, Section 4. OECD Publishing, Paris. doi:10.1787/9789264071100-en
OECD (2014). The Adverse Outcome Pathway for Skin Sensitisation Initiated by Covalent Binding to Proteins. OECD Series on Testing and Assessment, No. 168. OECD Publishing, Paris. doi:10.1787/9789264221444-en
OECD (2018a). Test No. 442D: In Vitro Skin Sensitisation: ARE-Nrf2 Luciferase Test Method. OECD Guidelines for the Testing of Chemicals, Section 4. OECD Publishing, Paris. doi:10.1787/9789264229822-en
OECD (2021a). Test No. 406: Skin Sensitisation. OECD Guidelines for the Testing of Chemicals, Section 4. OECD Publishing, Paris. doi:10.1787/9789264070660-en
OECD (2021b). Test No. 442C: In Chemico Skin Sensitisation: Assays addressing the Adverse Outcome Pathway key event on covalent binding to proteins. OECD Guidelines for the Testing of Chemicals, Section 4. OECD Publishing, Paris. doi:10.1787/9789264229709-en
OECD (2021c). Guideline No. 497: Defined Approaches on Skin Sensitisation. OECD Guidelines for the Testing of Chemicals, Section 4. OECD Publishing, Paris. doi:10.1787/b92879a4-en
OECD (2022). Test No. 442E: In Vitro Skin Sensitisation: In Vitro Skin Sensitisation assays addressing the Key Event on activation of dendritic cells on the Adverse Outcome Pathway for Skin Sensitisation. OECD Guidelines for the Testing of Chemicals, Section 4. OECD Publishing, Paris. doi:10.1787/9789264264359-en
Phipson, B., Lee, S., Majewski, I. J. et al. (2016). Robust hyperparameter estimation protects against hyervariable genes and improves power to detect differential expression. Ann Appl Stat 10, 946-963. doi:10.1214/16-AOAS920
Rachmawati, D., Bontkes, H. J., Verstege, M. I. et al. (2013). Transition metal sensing by Toll-like receptor-4: Next to nickel, cobalt and palladium are potent human dendritic cell stimulators. Contact Dermatitis 68, 331-338. doi:10.1111/cod.12042
Riedel, F., Aparicio-Soto, M., Curato, C. et al. (2021). Immunological mechanisms of metal allergies and the nickel-specific TCR-pMHC interface. Int J Environ Res Public Health 18, 10867. doi:10.3390/ijerph182010867
Ritchie, M. E., Phipson, B., Wu, D. et al. (2015). Limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res 43, e47. doi:10.1093/nar/gkv007
Schmidt, M., Raghavan, B., Müller, V. et al. (2010). Crucial role for human Toll-like receptor 4 in the development of contact allergy to nickel. Nat Immunol 11, 814-819. doi:10.1038/ni.1919
Schuttelaar, M. L. A., Ofenloch, R. F., Bruze, M. et al. (2018). Prevalence of contact allergy to metals in the European general population with a focus on nickel and piercings: The EDEN fragrance study. Contact Derm 79, 1-9. doi:10.1111/cod.12983
Strickland, J., Daniel, A. B., Allen, D. et al. (2019). Skin sensitization testing needs and data uses by US regulatory and research agencies. Arch Toxicol 93, 273-291. doi:10.1007/s00204-018-2341-6
Strickland, J., Truax, J., Corvaro, M. et al. (2022). Application of defined approaches for skin sensitization to agrochemical products. Front Toxicol 4, 852856. doi:10.3389/ftox.2022.852856
Sullivan, K., Enoch, S., Ezendam, J. et al. (2017). An adverse outcome pathway for sensitization of the respiratory tract by low-molecular-weight chemicals: Building evidence to support the utility of in vitro and in silico methods in a regulatory context. Appl In Vitro Toxicol 3, 213-226. doi:10.1089/aivt.2017.0010
Urbisch, D., Mehling, A., Guth, K. et al. (2015). Assessing skin sensitization hazard in mice and men using non-animal test methods. Regul Toxicol Pharmacol 71, 337-351. doi:10.1016/j.yrtph.2014.12.008
Uter, W., Werfel, T., Lepoittevin, J. P. et al. (2020). Contact allergy-emerging allergens and public health impact. Int J Environ Res Public Health 17, 2404. doi:10.3390/ijerph17072404