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

Ball, Nicholas; Cagen, Stuart Z.; Carrillo, Juan-Carlos; Certa, Hans; Eigler, Dorothea; Emter, Roger; Faulhammer, Frank; Garcia, Christine; Graham, Cynthia; Haux, Carl; Kolle, Susanne N.; Kreiling, Reinhard; Natsch, Andreas; Mehling, Annette

doi:10.1016/j.yrtph.2011.05.007

Cited by 70 publications

(33 citation statements)

References 29 publications

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“…The KeratinoSens™ assay has been tested against a broad range of low molecular weight chemicals with known skin sensitization potential (Ball et al 2011;Delaine et al 2011Delaine et al , 2014Emter et al 2010;Natsch et al 2013aNatsch et al , b, 2015O'Boyle et al 2012;Urbisch et al 2015), and it was found to respond to skin sensitizers from a broad range of socalled mechanistic applicability domains, i.e., chemicals reacting with proteins by different mechanisms.…”

Section: Predictivity For Animal Datamentioning

confidence: 99%

“…Thus, the LLNA often classifies irritating surfactants as positives, while they are (1) not reported as human sensitizers, (2) clearly negative in the guinea pig assays and (3) devoid of any structural alerts for reactivity and sensitization. A series of such "LLNA falsepositive" surfactants was "correct-negative" when tested in KeratinoSens™ (Ball et al 2011). On the other hand, some Michael acceptors (α, β-unsaturated compounds) are reported as negative in the LLNA despite clear structural alerts, direct peptide reactivity and positive human data.…”

Section: Predictivity For Animal Datamentioning

confidence: 99%

“…Putative pre-and prohaptens tested in different approaches to enhance metabolic capacity of the KeratinoSens™ assay (KS) (Natsch and Haupt 2013) and of an LC-MS-based peptide reactivity assay (Ball et al 2011;Natsch and Gfeller 2008). Results from Natsch and Haupt (2013) and unpublished observations Implementing reporter assays into integrated testing strategies…”

Section: Figmentioning

confidence: 99%

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Reporter cell lines for skin sensitization testing

Natsch

Emter

2015

Arch Toxicol

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Skin sensitization has been described as an adverse outcome pathway (AOP), comprising a number of molecular events leading to the final adverse effect. In a new paradigm of toxicology, attempts are made to collect information using single mechanistic tests addressing different targets along such an AOP and to then integrate this information to arrive at a final toxicological prediction. This proposal is strongly influenced by the availability of methods for high-throughput screening of cellular events. Reporter cell lines are a particularly useful tool in such screening paradigms, as they can deliver highly reproducible and easily measureable results, and they can be designed to quantify induction or suppression at the transcription level of very specific molecular targets within cells. The first cell-based assay for skin sensitization, which has recently received ECVAM and OECD endorsement, is the reporter cell assay KeratinoSens™, reflecting activation of the Nrf2 pathway, and other assays measuring the Nrf2 pathway are under development or validation. An alternative approach (THP-G8) was recently developed based on activation of the Interleukin-8 gene. Here, we review these assays, their role in the AOP, their mechanistic interrelationships, their use for hazard and risk assessment, and their application in integrated testing strategies. At the same time, this study reviews (1) other cellular markers for sensitizers, and the potential to develop new reporter gene assays providing additional, non-redundant information, and (2) it presents approaches and new experimental data on attempts to further improve the predictivity of the existing assay.

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Section: Predictivity For Animal Datamentioning

confidence: 99%

Section: Predictivity For Animal Datamentioning

confidence: 99%

Section: Figmentioning

confidence: 99%

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Reporter cell lines for skin sensitization testing

Natsch

Emter

2015

Arch Toxicol

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“…The mouse in vivo local lymph node assay (LLNA) is currently the preferred test for predicting the skin sensitization potential of novel chemicals (OECD, 2010;Ball et al, 2011). Not only does the OECD Test Guideline (TG) 429 recommend using the LLNA method to predict skin sensitization potential for novel chemicals, it also provides a reference chemical list of human skin irritants and sensitizers.…”

Section: Nhks Produce Vegf and Il-8 In Response To Pro-inflammatory Cmentioning

confidence: 99%

Chemical allergens stimulate human epidermal keratinocytes to produce lymphangiogenic vascular endothelial growth factor

Bae

Ahn

Sun

et al. 2015

Toxicology and Applied Pharmacology

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“…Even though the LLNA is validated as a stand-alone assay for sensitization testing, there are several drawbacks to it such as false positives, e.g., irritants, and false negatives, e.g., metal allergens (Ikarashi et al 1992(Ikarashi et al , 1993Montelius et al 1994;Mandervelt et al 1997;Montelius et al 1998;Vohr and Ahr 2005;Basketter et al 2009;Ball et al 2011). Interesting results were shown for an array of mostly Abstract Unsaturated compounds are known to cause false-positive reactions in the local lymph node assay (LLNA) but not in the guinea pig maximization test.…”

Section: Introductionmentioning

confidence: 99%

Unsaturated compounds induce up-regulation of CD86 on dendritic cells in the in vitro sensitization assay LCSA

et al. 2015

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Unsaturated compounds are known to cause false-positive reactions in the local lymph node assay (LLNA) but not in the guinea pig maximization test. We have tested a panel of substances (succinic acid, undecylenic acid, 1-octyn-3-ol, fumaric acid, maleic acid, linoleic acid, oleic acid, alpha-linolenic acid, squalene, and arachidonic acid) in the loose-fit coculture-based sensitization assay (LCSA) to evaluate whether unspecific activation of dendritic cells is a confounder for sensitization testing in vitro. Eight out of 10 tested substances caused significant up-regulation of CD86 on dendritic cells cocultured with keratinocytes and would have been classified as sensitizers; only succinic acid was tested negative, and squalene had to be excluded from data analysis due to poor solubility in cell culture medium. Based on human data, only undecylenic acid can be considered a true sensitizer. The true sensitizing potential of 1-octyn-3-ol is uncertain. Fumaric acid and its isomer maleic acid are not known as sensitizers, but their esters are contact allergens. A group of 18- to 20-carbon chain unsaturated fatty acids (linoleic acid, oleic acid, alpha-linolenic acid, and arachidonic acid) elicited the strongest reaction in vitro. This is possibly due to the formation of pro-inflammatory lipid mediators in the cell culture causing nonspecific activation of dendritic cells. In conclusion, both the LLNA and the LCSA seem to provide false-positive results for unsaturated fatty acids. The inclusion of T cells in dendritic cell-based in vitro sensitization assays may help to eliminate false-positive results due to nonspecific dendritic cell activation. This would lead to more accurate prediction of sensitizers, which is paramount for consumer health protection and occupational safety.

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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

Cited by 70 publications

References 29 publications

Reporter cell lines for skin sensitization testing

Reporter cell lines for skin sensitization testing

Chemical allergens stimulate human epidermal keratinocytes to produce lymphangiogenic vascular endothelial growth factor

Unsaturated compounds induce up-regulation of CD86 on dendritic cells in the in vitro sensitization assay LCSA

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