Evaluation of an<i>In Vitro</i>Human Dermal Sensitization Test for Use with Medical Device Extracts

Coleman, Kelly P.; McNamara, Lori R.; Grailer, Thomas; Willoughby, Jamin A.; Keller, Donald J.; Patel, Prakash; Thomas, Simon; Dilworth, Clive

doi:10.1089/aivt.2015.0007

Cited by 16 publications

(12 citation statements)

References 31 publications

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“…Similarly, EpiDerm™, EpiSkin™, SkinEthic™ and LabCyte™ models are considered as acceptable setups for skin irritation testing (OECD TG 439 (OECD, 2013)). A validation study addressing the skin irritation and sensitization potency of extracts from medical devices is furthermore underway (Casas et al, 2013;ISO, 2010;Coleman et al, 2015). Another example for the successful use of RhE is the phototoxicity assessment of topically applied substances and formulations, as demonstrated in the pre-validation study of the EpiDerm™ model (Liebsch et al, 1999).…”

Section: Tab 1: Models For Dermal Absorptionmentioning

confidence: 99%

Non-animal models of epithelial barriers (skin, intestine and lung) in research, industrial applications and regulatory toxicology

Gordon

Daneshian

Bouwstra

et al. 2015

ALTEX

124

103

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SummaryModels of the outer epithelia of the human body -namely the skin, the intestine and the lung -have found valid applications in both research and industrial settings as attractive alternatives to animal testing. A variety of approaches to model these barriers are currently employed in such fields, ranging from the utilization of ex vivo tissue to reconstructed in vitro models, and further to chip-based technologies, synthetic membrane systems and, of increasing current interest, in silico modeling approaches. An international group of experts in the field of epithelial barriers was convened from academia, industry and regulatory bodies to present both the current state of the art of non-animal models of the skin, intestinal and pulmonary barriers in their various fields of application, and to discuss research-based, industry-driven and regulatory-relevant future directions for both the development of new models and the refinement of existing test methods. Issues of model relevance and preference, validation and standardization, acceptance, and the need for simplicity versus complexity were focal themes of the discussions. The outcomes of workshop presentations and discussions, in relation to both current status and future directions in the utilization and development of epithelial barrier models, are presented by the attending experts in the current report.

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Section: Tab 1: Models For Dermal Absorptionmentioning

confidence: 99%

Non-animal models of epithelial barriers (skin, intestine and lung) in research, industrial applications and regulatory toxicology

Gordon

Daneshian

Bouwstra

et al. 2015

ALTEX

124

103

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“…To assess skin sensitization of medical devices, McKim and colleagues tested different vehicles spiked with sensitizers and showed responses of skin models (Epiderm and SkinEthik) towards the applied testing matrix [29]. Furthermore, Coleman and colleagues integrated skin sensitizers in silicone samples and could demonstrate a reaction of skin models (SenCeeTox) towards the extracts [15]. By assessing various endpoints they could detect skin sensitizers in silicone samples at a concentration of 10% w/w.…”

Section: Discussionmentioning

confidence: 99%

“…The strategy of using polar as well as non-polar extraction methods as in ISO 10993-12:2012 [32] is of great importance because several samples in our assay only tested positive in one of the extracts. Different reactivity in polar (saline) and non-polar (sesame oil) extracts was also described for the SenCeeTox assay [15].…”

Section: Discussionmentioning

confidence: 99%

“…In 2016 the h-Clat assay was added [6]. However, these assays have only been validated for pure chemicals, whereas extracts of medical devices are still undergoing animal testing [15].…”

Section: Introductionmentioning

confidence: 99%

“…However, in vitro assays are not the only available information source for the evaluation of the safety of substances but form part of a weight of evidence approach in an integrated testing strategy (ITS) [17]. As sensitization itself is the result of various complex events, many researchers believe that no single test alone can predict all human sensitizers [15]. While animal tests screen the whole sensitization process, alternative in vitro testing methods are focused on various different key events of the adverse outcome pathway (AOP) starting with an initial binding of haptens to proteins leading to activation of keratinocytes and dendritic cells and proliferation of T-cells and finally the manifestation as allergic contact dermatitis [18].…”

Section: Introductionmentioning

confidence: 99%

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A dual luciferase assay for evaluation of skin sensitizing potential of medical devices

et al. 2019

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According to standing regulations animal tests are still state of the art for the evaluation of the sensitization potential of medical devices. The aim of our study was to develop an in vitro method that can be used for testing of extracts of medical devices. The novel MDA-ARE assay is a cell based reporter gene assay focused on the ARE-Nrf2 pathway, which is involved in the dermal sensitization process. Optimization of the reporter construct and the cell line resulted in an improvement of the detection limit and a reduction of the incubation time to 6 h, which lowers cytotoxic side effects of the extracts on the cells. Using the assay, 21 out of 22 pure chemicals were identified correctly as skin sensitizers or non-sensitizers. All sensitizers could be detected at far lower concentrations compared to the local lymph node assay, the state-of-the-art animal test. To evaluate the assay's suitability for the testing of medical devices, medical grade silicone containing 0.1% of known skin sensitizers was prepared as positive controls and extracts of these positive controls were tested in comparison to extracts from pure silicone samples. All silicone samples were correctly and reproducibly identified as sensitizing or non-sensitizing demonstrating that the MDA-ARE assay is a sensitive and reliable tool for the detection of skin sensitizers in extracts of medical devices. The developed and validated test protocol was used for medical device extracts and showed its applicability for real samples and thus can contribute to reduce or even to replace the need for animal tests.

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State of the art in non-animal approaches for skin sensitization testing: from individual test methods towards testing strategies

2016

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The hazard assessment of skin sensitizers relies mainly on animal testing, but much progress is made in the development, validation and regulatory acceptance and implementation of non-animal predictive approaches. In this review, we provide an update on the available computational tools and animal-free test methods for the prediction of skin sensitization hazard. These individual test methods address mostly one mechanistic step of the process of skin sensitization induction. The adverse outcome pathway (AOP) for skin sensitization describes the key events (KEs) that lead to skin sensitization. In our review, we have clustered the available test methods according to the KE they inform: the molecular initiating event (MIE/KE1)-protein binding, KE2-keratinocyte activation, KE3-dendritic cell activation and KE4-T cell activation and proliferation. In recent years, most progress has been made in the development and validation of in vitro assays that address KE2 and KE3. No standardized in vitro assays for T cell activation are available; thus, KE4 cannot be measured in vitro. Three non-animal test methods, addressing either the MIE, KE2 or KE3, are accepted as OECD test guidelines, and this has accelerated the development of integrated or defined approaches for testing and assessment (e.g. testing strategies). The majority of these approaches are mechanism-based, since they combine results from multiple test methods and/or computational tools that address different KEs of the AOP to estimate skin sensitization potential and sometimes potency. Other approaches are based on statistical tools. Until now, eleven different testing strategies have been published, the majority using the same individual information sources. Our review shows that some of the defined approaches to testing and assessment are able to accurately predict skin sensitization hazard, sometimes even more accurate than the currently used animal test. A few defined approaches are developed to provide an estimate of the potency sub-category of a skin sensitizer as well, but these approaches need further independent evaluation with a new dataset of chemicals. To conclude, this update shows that the field of non-animal approaches for skin sensitization has evolved greatly in recent years and that it is possible to predict skin sensitization hazard without animal testing.

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Evaluation of anIn VitroHuman Dermal Sensitization Test for Use with Medical Device Extracts

Cited by 16 publications

References 31 publications

Non-animal models of epithelial barriers (skin, intestine and lung) in research, industrial applications and regulatory toxicology

Non-animal models of epithelial barriers (skin, intestine and lung) in research, industrial applications and regulatory toxicology

A dual luciferase assay for evaluation of skin sensitizing potential of medical devices

State of the art in non-animal approaches for skin sensitization testing: from individual test methods towards testing strategies

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