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Toxics
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Skin Sensitization Testing Using New Approach Methodologies
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Skin Sensitization Testing Using New Approach Methodologies

A special issue of Toxics (ISSN 2305-6304). This special issue belongs to the section "Novel Methods in Toxicology Research".

Deadline for manuscript submissions: closed (19 July 2024) | Viewed by 9053

Special Issue Editor

Dr. Judy Strickland

E-Mail Website
Guest Editor
Inotiv, Inc., P.O. Box 13501, Research Triangle Park, NC 27709, USA
Interests: contact dermatitis; validation; method development; toxicity tests; prediction; cytotoxicity assays; toxicology; validation studies toxicity

Special Issue Information

Dear Colleagues,

At present,  the skin sensitization testing of chemical substances and products on the market can be conducted without animal testing. Integrating the results of individual test methods using defined approaches makes it possible to derive regulatory classifications for skin sensitization hazard or potency. Defined approaches that can be used for risk assessments to determine safe levels of sensitizers that are expected to be approved for regulatory use in the near future. This special edition seeks contributions that explore the application of new approach methodologies to overcome the regulatory challenges of assessing skin sensitization. These new approach methodologies include in chemico, in vitro, in silico, and other non-animal approaches and strategies that combine the outcomes of such methods. Interesting topics include, but are not limited to, the testing of mixtures (chemical products or medical device extracts, for example) for skin sensitization hazard or potency classification, test method development, and the evaluation of new methods, such as those to predict T cell proliferation, the development and use of appropriate reference data for evaluations, and the development of new defined approaches.

Dr. Judy Strickland
Guest Editor

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Keywords

  • skin sensitization
  • alternatives to animal testing
  • regulatory testing
  • reference data
  • defined approaches
  • chemical allergy
  • new approach methodologies
  • adverse outcome pathway

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Published Papers (7 papers)

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Research

18 pages, 1206 KiB  
Article
Increasing Accessibility of Bayesian Network-Based Defined Approaches for Skin Sensitisation Potency Assessment
by Tomaz Mohoric, Anke Wilm, Stefan Onken, Andrii Milovich, Artem Logavoch, Pascal Ankli, Ghada Tagorti, Johannes Kirchmair, Andreas Schepky, Jochen Kühnl, Abdulkarim Najjar, Barry Hardy and Johanna Ebmeyer
Toxics 2024, 12(9), 666; https://doi.org/10.3390/toxics12090666 - 12 Sep 2024
Viewed by 1100
Abstract
Skin sensitisation is a critical adverse effect assessed to ensure the safety of compounds and materials exposed to the skin. Alongside the development of new approach methodologies (NAMs), defined approaches (DAs) have been established to promote skin sensitisation potency assessment by adopting and [...] Read more.
Skin sensitisation is a critical adverse effect assessed to ensure the safety of compounds and materials exposed to the skin. Alongside the development of new approach methodologies (NAMs), defined approaches (DAs) have been established to promote skin sensitisation potency assessment by adopting and integrating standardised in vitro, in chemico, and in silico methods with specified data analysis procedures to achieve reliable and reproducible predictions. The incorporation of additional NAMs could help increase accessibility and flexibility. Using superior algorithms may help improve the accuracy of hazard and potency assessment and build confidence in the results. Here, we introduce two new DA models, with the aim to build DAs on freely available software and the newly developed kDPRA for covalent binding of a chemical to skin peptides and proteins. The new DA models are built on an existing Bayesian network (BN) modelling approach and expand on it. The new DA models include kDPRA data as one of the in vitro parameters and utilise in silico inputs from open-source QSAR models. Both approaches perform at least on par with the existing BN DA and show 63% and 68% accuracy when predicting four LLNA potency classes, respectively. We demonstrate the value of the Bayesian network’s confidence indications for predictions, as they provide a measure for differentiating between highly accurate and reliable predictions (accuracies up to 87%) in contrast to low-reliability predictions associated with inaccurate predictions. Full article
(This article belongs to the Special Issue Skin Sensitization Testing Using New Approach Methodologies)
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16 pages, 1256 KiB  
Article
In Vitro Prediction of Skin-Sensitizing Potency Using the GARDskin Dose–Response Assay: A Simple Regression Approach
by Robin Gradin, Fleur Tourneix, Ulrika Mattson, Johan Andersson, Frédéric Amaral, Andy Forreryd, Nathalie Alépée and Henrik Johansson
Toxics 2024, 12(9), 626; https://doi.org/10.3390/toxics12090626 - 24 Aug 2024
Viewed by 889
Abstract
Toxicological assessments of skin sensitizers have progressed towards a higher reliance on non-animal methods. Current technological trends aim to extend the utility of non-animal methods to accurately characterize skin-sensitizing potency. The GARDskin Dose–Response assay has previously been described; it was shown that its [...] Read more.
Toxicological assessments of skin sensitizers have progressed towards a higher reliance on non-animal methods. Current technological trends aim to extend the utility of non-animal methods to accurately characterize skin-sensitizing potency. The GARDskin Dose–Response assay has previously been described; it was shown that its main readout, cDV0 concentration, is associated with skin-sensitizing potency. The ability to predict potency from cDV0 in the form of NESILs derived from LLNAs or human NOELs was evaluated. The assessment of a dataset of 30 chemicals showed that the cDV0 values still correlated strongly and significantly with both LLNA EC3 and human NOEL values (ρ = 0.645–0.787 [p < 1 × 10−3]). A composite potency value that combined LLNA and human potency data was defined, which aided the performance of the proposed model for the prediction of NESILs. The potency model accurately predicted sensitizing potency, with cross-validation errors of 2.75 and 3.22 fold changes compared with NESILs from LLNAs and humans, respectively. In conclusion, the results suggest that the GARDskin Dose–Response assay may be used to derive an accurate quantitative continuous potency estimate of skin sensitizers. Full article
(This article belongs to the Special Issue Skin Sensitization Testing Using New Approach Methodologies)
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16 pages, 301 KiB  
Article
Limitations and Modifications of Skin Sensitization NAMs for Testing Inorganic Nanomaterials
by Britta Wareing, Ayse Aktalay Hippchen, Susanne N. Kolle, Barbara Birk, Dorothee Funk-Weyer and Robert Landsiedel
Toxics 2024, 12(8), 616; https://doi.org/10.3390/toxics12080616 - 21 Aug 2024
Viewed by 1029
Abstract
Since 2020, the REACh regulation requires toxicological data on nanoforms of materials, including the assessment of their skin-sensitizing properties. Small molecules’ skin sensitization potential can be assessed by new approach methodologies (NAMs) addressing three key events (KE: protein interaction, activation of dendritic cells, [...] Read more.
Since 2020, the REACh regulation requires toxicological data on nanoforms of materials, including the assessment of their skin-sensitizing properties. Small molecules’ skin sensitization potential can be assessed by new approach methodologies (NAMs) addressing three key events (KE: protein interaction, activation of dendritic cells, and activation of keratinocytes) combined in a defined approach (DA) described in the OECD guideline 497. In the present study, the applicability of three NAMs (DPRA, LuSens, and h-CLAT) to nine materials (eight inorganic nanomaterials (NM) consisting of CeO2, BaSO4, TiO2 or SiO2, and quartz) was evaluated. The NAMs were technically applicable to NM using a specific sample preparation (NANOGENOTOX dispersion protocol) and method modifications to reduce interaction of NM with the photometric and flowcytometric read-outs. The results of the three assays were combined according to the defined approach described in the OECD guideline No. 497; two of the inorganic NM were identified as skin sensitizers. However, data from animal studies (for ZnO, also human data) indicate no skin sensitization potential. The remaining seven test substances were assessed as “inconclusive” because all inorganic NM were outside the domain of the DPRA, and the achievable test concentrations were not sufficiently high according to the current test guidelines of all three NAMs. The use of these NAMs for (inorganic) NM and the relevance of the results in general are challenged in three ways: (i) NAMs need modification to be applicable to insoluble, inorganic matter; (ii) current test guidelines lack adequate concentration metrics and top concentrations achievable for NM; and (iii) NM may not cause skin sensitization by the same molecular and cellular key events as small organic molecules do; in fact, T-cell-mediated hypersensitivity may not be the most relevant reaction of the immune system to NM. We conclude that the NAMs adopted by OECD test guidelines are currently not a good fit for testing inorganic NM. Full article
(This article belongs to the Special Issue Skin Sensitization Testing Using New Approach Methodologies)
16 pages, 1569 KiB  
Article
Deriving a Continuous Point of Departure for Skin Sensitization Risk Assessment Using a Bayesian Network Model
by Fleur Tourneix, Leopold Carron, Lionel Jouffe, Sebastian Hoffmann and Nathalie Alépée
Toxics 2024, 12(8), 536; https://doi.org/10.3390/toxics12080536 - 24 Jul 2024
Viewed by 701
Abstract
Regulations of cosmetic ingredients and products have been the most advanced in embracing new approach methodologies (NAMs). Consequently, the cosmetic industry has assumed a forerunner role in the development and implementation of animal-free next-generation risk assessment (NGRA) that incorporates defined approaches (DAs) to [...] Read more.
Regulations of cosmetic ingredients and products have been the most advanced in embracing new approach methodologies (NAMs). Consequently, the cosmetic industry has assumed a forerunner role in the development and implementation of animal-free next-generation risk assessment (NGRA) that incorporates defined approaches (DAs) to assess the skin sensitization potency of ingredients. A Bayesian network DA predicting four potency categories (SkinSens-BN) was constructed against reference Local Lymph Node Assay data for a total of 297 substances, achieving a predictive performance similar to that of other DAs. With the aim of optimally informing risk assessment with a continuous point of departure (PoD), a weighted sum of the SkinSens-BN probabilities for four potency classes (non-, weak, moderate, and strong/extreme sensitizer) was calculated, using fixed weights based on associated LLNA EC3-values. The approach was promising, e.g., the derived PoDs for substances classified as non-sensitizers did not overlap with any others and 77% of PoDs were similar or more conservative than LLNA EC3. In addition, the predictions were assigned a level of confidence based on the probabilities to inform the evaluation of uncertainty in an NGRA context. In conclusion, the PoD derivation approach can substantially contribute to reliable skin sensitization NGRAs. Full article
(This article belongs to the Special Issue Skin Sensitization Testing Using New Approach Methodologies)
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16 pages, 2204 KiB  
Article
Evaluation of the Safety of Cosmetic Ingredients and Their Skin Compatibility through In Silico and In Vivo Assessments of a Newly Developed Eye Serum
by Anca Maria Juncan, Luca-Liviu Rus, Claudiu Morgovan and Felicia Loghin
Toxics 2024, 12(7), 451; https://doi.org/10.3390/toxics12070451 - 22 Jun 2024
Viewed by 1308
Abstract
The term “risk assessment” is often substituted with “safety assessment”, to demonstrate the safe properties of cosmetic ingredients and formulations. With respect to the actual legislative framework, the proper use of in silico evaluation could offer a representative non-animal substitute for the toxicity [...] Read more.
The term “risk assessment” is often substituted with “safety assessment”, to demonstrate the safe properties of cosmetic ingredients and formulations. With respect to the actual legislative framework, the proper use of in silico evaluation could offer a representative non-animal substitute for the toxicity evaluation of cosmetic ingredients. The in silico assessment needs to be integrated with other lines of proof (in vitro and/or in vivo data) in the form of a complex methodology in order to demonstrate the safety evaluation of cosmetic ingredients/products. The present study aimed to develop and characterize a new cosmetic formulation, designed for the skin care of the periorbital area. Quality control comprising stability, physicochemical, and microbiological evaluation was performed. Another objective of this study was to present a screening model for the safety evaluation of the cosmetic formulation by identifying individual ingredients, and to confirm the skin compatibility based on in vivo evaluation. The results demonstrated the in silico and in vivo safety profile of the cosmetic ingredients used in the present formulation. In silico evaluation, using a novel, specific software applicable for the risk evaluation of ingredients and formulations, showed that the incorporated ingredients were non-mutagenic and non-sensitizing, and considering the margin of safety (MoS), the cosmetic raw materials could be considered safe. Skin compatibility was confirmed by the patch test performed under dermatological control, evidencing the “non-irritating” potential of the developed cosmetic formulation. Full article
(This article belongs to the Special Issue Skin Sensitization Testing Using New Approach Methodologies)
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15 pages, 2535 KiB  
Article
An In Vitro Human Skin Test for Predicting Skin Sensitization and Adverse Immune Reactions to Biologics
by Shaheda Sameena Ahmed, Mohammed Mahid Ahmed, Abbas Ishaq, Matthew Freer, Richard Stebbings and Anne Mary Dickinson
Toxics 2024, 12(6), 401; https://doi.org/10.3390/toxics12060401 - 30 May 2024
Cited by 2 | Viewed by 1159
Abstract
Biologics, including monoclonal antibodies (mAb), have proved to be effective and successful therapeutic agents, particularly in the treatment of cancer and immune-inflammatory conditions, as well as allergies and infections. However, their use carries an inherent risk of an immune-mediated adverse drug reaction. In [...] Read more.
Biologics, including monoclonal antibodies (mAb), have proved to be effective and successful therapeutic agents, particularly in the treatment of cancer and immune-inflammatory conditions, as well as allergies and infections. However, their use carries an inherent risk of an immune-mediated adverse drug reaction. In this study, we describe the use of a novel pre-clinical human in vitro skin explant test for predicting skin sensitization and adverse immune reactions. The skin explant test was used to investigate the effects of therapeutic antibodies, which are known to cause a limited reaction in a small number of patients or more severe reactions. Material and Methods: Immune responses were determined by T cell proliferation and multiplex cytokine analysis, as well as histopathological analysis of skin damage (grades I–IV in increasing severity), predicting a negative (grade I) or positive (grade ≥ II) response for an adverse skin sensitization effect. Results: T cell proliferation responses were significantly increased in the positive group (p < 0.004). Multiplex cytokine analysis showed significantly increased levels of IFNγ, TNFα, IL-10, IL-12, IL-13, IL-1β, and IL-4 in the positive response group compared with the negative response group (p < 0.0001, p < 0.0001, p < 0.002, p < 0.01, p < 0.04, p < 0.006, and p < 0.004, respectively). Conclusions: Overall, the skin explant test correctly predicted the clinical outcome of 13 out of 16 therapeutic monoclonal antibodies with a correlation coefficient of 0.770 (p = 0.0001). This assay therefore provides a valuable pre-clinical test for predicting adverse immune reactions, including T cell proliferation and cytokine release, both associated with skin sensitization to monoclonal antibodies. Full article
(This article belongs to the Special Issue Skin Sensitization Testing Using New Approach Methodologies)
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17 pages, 6154 KiB  
Article
A Human Skin Explant Test as a Novel In Vitro Assay for the Detection of Skin Sensitization to Aggregated Monoclonal Antibodies
by Ana Martins-Ribeiro, Arathi Kizhedath, Shaheda Sameena Ahmed, Jarka Glassey, Abbas Ishaq, Matthew Freer and Anne Mary Dickinson
Toxics 2024, 12(5), 332; https://doi.org/10.3390/toxics12050332 - 30 Apr 2024
Cited by 1 | Viewed by 1539
Abstract
Introduction: Monoclonal antibodies (mAbs) are important therapeutics. However, the enhanced potential for aggregation has become a critical quality parameter during the production of mAbs. Furthermore, mAb aggregation may also present a potential health risk in a clinical setting during the administration of mAb [...] Read more.
Introduction: Monoclonal antibodies (mAbs) are important therapeutics. However, the enhanced potential for aggregation has become a critical quality parameter during the production of mAbs. Furthermore, mAb aggregation may also present a potential health risk in a clinical setting during the administration of mAb therapeutics to patients. While the extent of immunotoxicity in patient populations is uncertain, reports show it can lead to immune responses via cell activation and cytokine release. In this study, an autologous in vitro skin test designed to predict adverse immune events, including skin sensitization, was used as a novel assay for the assessment of immunotoxicity caused by mAb aggregation. Material and Methods: Aggregation of mAbs was induced by a heat stress protocol, followed by characterization of protein content by analytical ultra-centrifugation and transmission electron microscopy, revealing a 4% aggregation level of total protein content. Immunotoxicity and potential skin sensitization caused by the aggregates, were then tested in a skin explant assay. Results: Aggregated Herceptin and Rituximab caused skin sensitization, as shown by histopathological damage (grade II–III positive response) together with positive staining for Heat Shock Protein 70 (HSP70). Changes in T cell proliferation were not observed. Cytokine analysis revealed a significant increase of IL-10 for the most extreme condition of aggregation (65 °C at pH3) and a trend for an overall increase of IFN-γ, especially in response to Rituximab. Conclusions: The skin explant assay demonstrated that aggregated mAbs showed adverse immune reactions, as demonstrated as skin sensitization, with histopathological grades II-III. The assay may, therefore, be a novel tool for assessing immunotoxicity and skin sensitization caused by mAb aggregation. Full article
(This article belongs to the Special Issue Skin Sensitization Testing Using New Approach Methodologies)
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