title: Evaluating the performance of integrated approaches for hazard identification of skin sensitizing chemicals.
abstract: The currently available animal-free methods for the detection of skin sensitizing potential of chemicals seem promising. However, no single method is able to comprehensively represent the complexity of the processes involved in skin sensitization. To ensure a mechanistic basis and cover the complexity, multiple methods should be integrated into a testing strategy, in accordance with the adverse outcome pathway that describes all key events in skin sensitization. Although current majority voting testing strategies have proven effective, the performance of individual methods is not taken into account. To that end, we designed a tiered strategy based on complementary characteristics of the included methods, and compared it to a majority voting approach. This tiered testing strategy was able to correctly identify all 41 chemicals tested. In terms of total number of experiments required, the tiered testing strategy requires less experiments compared to the majority voting approach. On the other hand, this tiered strategy is more complex due the number of different alternative methods required, and predicted costs are similar for both strategies. Both the tiered and majority voting strategies provide a mechanistic basis for skin sensitization testing, but the strategy most suitable for regulatory decision-making remains to be determined.
authors.affiliation: National Institute for Public Health and the Environment (RIVM), PO Box 1, NL-3720BA Bilthoven, The Netherlands; Department of Toxicogenomics, Maastricht University, PO Box 616, NL-6200 MD Maastricht, The Netherlands.
authors.forename: Jochem W
authors.initials: JW
authors.lastname: van der Veen
authors.affiliation: National Institute for Public Health and the Environment (RIVM), PO Box 1, NL-3720BA Bilthoven, The Netherlands.
authors.forename: Emiel
authors.initials: E
authors.lastname: Rorije
authors.affiliation: Givaudan Schweiz AG, Ueberlandstrasse 138, CH-8600 Dübendorf, Switzerland.
authors.forename: Roger
authors.initials: R
authors.lastname: Emter
authors.affiliation: Givaudan Schweiz AG, Ueberlandstrasse 138, CH-8600 Dübendorf, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Natsch
authors.affiliation: National Institute for Public Health and the Environment (RIVM), PO Box 1, NL-3720BA Bilthoven, The Netherlands; Department of Toxicogenomics, Maastricht University, PO Box 616, NL-6200 MD Maastricht, The Netherlands.
authors.forename: Henk
authors.initials: H
authors.lastname: van Loveren
authors.affiliation: National Institute for Public Health and the Environment (RIVM), PO Box 1, NL-3720BA Bilthoven, The Netherlands. Electronic address: Janine.ezendam@rivm.nl.
authors.forename: Janine
authors.initials: J
authors.lastname: Ezendam
mesh_terms: D000826:Animal Testing Alternatives / Q000379:methods*; D002460:Cell Line; D015386:Hazardous Substances / Q000009:adverse effects* / Q000737:chemistry*; D006801:Humans; D012867:Skin / Q000187:drug effects*; D012882:Skin Tests / Q000379:methods*
chemical_list: D015386:Hazardous Substances
keywords: Adverse outcome pathway; Allergic contact dermatitis; Animal-free testing; DPRA; Integrated testing strategy; Keratinocytes; LLNA; QSAR; Skin sensitization