Peptide reactivity associated with skin sensitization: The QSAR Toolbox and TIMES compared to the DPRA

Urbisch, Daniel; Honarvar, Naveed; Kolle, Susanne N.; Mehling, A.; Ramı́rez, Tzutzuy; Teubner, Wera; Landsiedel, Robert

doi:10.1016/j.tiv.2016.04.005

Cited by 32 publications

(26 citation statements)

References 36 publications

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“…19 also gave a negative response in KeratinoSens. However, a positive KeratinoSens result for the structurally highly similar dihydroeugenol (data published elsewhere) 14 indicates no general lack in detecting chemicals with similar reaction mechanisms as 19. The true positive result for 19 in the h-CLAT was due to mechanisms other than those detected by DPRA and KeratinoSens, and may indeed be linked to the specific key event addressed by this assay.…”

Section: Chemical Research In Toxicologymentioning

confidence: 94%

“…43 2-Methoxy-4-methylphenol (19) was negative in the DPRA and KeratinoSens but positive in the h-CLAT. 14 19 is a moderate sensitizer in the LLNA (EC3 = 5.8) 44 and positive in a HRIPT (compare RIFM database) and can possibly form an ortho-quinone or a para-quinone methide (Figure 8). In contrast to the formations of quinones and quinone imines, a demethylation of the methoxy group or the formation of a quinone methide might not occur under the conditions of the DPRA.…”

Section: Chemical Research In Toxicologymentioning

confidence: 99%

“…12,13 Recently, a comprehensive data compilation which reported a wealth of information on the use of these nonanimal test methods for distinguishing sensitizers from nonsensitizers was published. 14 The accuracies of the individual assays addressing the first three key events of the AOP are already good, but using combinations of these tests results in accuracy in predicting skin sensitization potential in humans which are comparable to or even exceed the accuracy of the LLNA. A simple but very effective prediction model is to use the results of the three nonanimal test methods in a 2 out of 3 weight of evidence (WoE) integrated testing strategy (ITS) approach, a so-called "fixed data interpretation procedure" (DIP) within an "integrated approach to testing and assessment" (IATA).…”

Section: Introductionmentioning

confidence: 99%

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Assessment of Pre- and Pro-haptens Using Nonanimal Test Methods for Skin Sensitization

Urbisch

Becker

Honarvar

et al. 2016

Chem. Res. Toxicol.

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Because of ethical and regulatory reasons, several nonanimal test methods to assess the skin sensitization potential of chemicals have been developed and validated. In contrast to in vivo methods, they lack or provide limited metabolic capacity. For this reason, identification of pro-haptens but also pre-haptens, which require molecular transformations to gain peptide reactivity, is a challenge for these methods. In this study, 27 pre- and pro-haptens were tested using nonanimal test methods. Of these, 18 provided true positive results in the direct peptide reactivity assay (DPRA; sensitivity of 67%), although lacking structural alerts for direct peptide reactivity. The reaction mechanisms leading to peptide depletion in the DPRA were therefore elucidated using mass spectrometry. Hapten-peptide adducts were identified for 13 of the 18 chemicals indicating that these pre-haptens were activated and that peptide binding occurred. Positive results for five of the 18 chemicals can be explained by dipeptide formations or the oxidation of the sulfhydryl group of the peptide. Nine of the 27 chemicals were tested negative in the DPRA. Of these, four yielded true positive results in the keratinocyte and dendritic cell based assays. Likewise, 16 of the 18 chemicals tested positive in the DPRA were also positive in either one or both of the cell-based assays. A combination of DPRA, KeratinoSens, and h-CLAT used in a 2 out of 3 weight of evidence (WoE) approach identified 22 of the 27 pre- and pro-haptens correctly (sensitivity of 81%), exhibiting a similar sensitivity as for directly acting haptens. This analysis shows that the combination of in chemico and in vitro test methods is suitable to identify pre-haptens and the majority of pro-haptens.

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Section: Chemical Research In Toxicologymentioning

confidence: 94%

Section: Chemical Research In Toxicologymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Assessment of Pre- and Pro-haptens Using Nonanimal Test Methods for Skin Sensitization

Urbisch

Becker

Honarvar

et al. 2016

Chem. Res. Toxicol.

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“…It is generally accepted that the three assays discussed here are intended to measure KEs in the skin sensitization AOP (OECD, , ). DPRA: covalent modification of skin protein (AOP KE 1, the MIE); KeratinoSens™: activation of keratinocytes (AOP KE 2); and h‐CLAT: activation of DCs (AOP KE 3) (Basketter et al, ; Urbisch et al, ). …”

Section: Discussionmentioning

confidence: 99%

“…This is one of the reasons why the DPRA + h-CLAT and KeratinoSens™ + h-CLAT binary combinations identified more sensitizers than the "two out of three" approach: two negatives arising from the shared metabolic deficiencies of the DPRA and KeratinoSens™ outweigh the positive result from the h-CLAT assay. An illustration is provided by results for a set of 27 pre-haptens and pro-hapten sensitizers, all positive in the LLNA, where the DPRA, KeratinoSens™ and h-CLAT results were reported by Urbisch et al (2016). For 18 of these substances, the DPRA was positive and at least one of the other two assays is positive.…”

Section: Causes Of Disagreementmentioning

confidence: 99%

Non‐animal assessment of skin sensitization hazard: Is an integrated testing strategy needed, and if so what should be integrated?

Roberts

Patlewicz

2017

J of Applied Toxicology

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There is an expectation that to meet regulatory requirements, and avoid or minimize animal testing, integrated approaches to testing and assessment will be needed that rely on assays representing key events (KEs) in the skin sensitization adverse outcome pathway. Three non-animal assays have been formally validated and regulatory adopted: the direct peptide reactivity assay (DPRA), the KeratinoSens™ assay and the human cell line activation test (h-CLAT). There have been many efforts to develop integrated approaches to testing and assessment with the "two out of three" approach attracting much attention. Here a set of 271 chemicals with mouse, human and non-animal sensitization test data was evaluated to compare the predictive performances of the three individual non-animal assays, their binary combinations and the "two out of three" approach in predicting skin sensitization potential. The most predictive approach was to use both the DPRA and h-CLAT as follows: (1) perform DPRA -if positive, classify as sensitizing, and (2) if negative, perform h-CLAT -a positive outcome denotes a sensitizer, a negative, a non-sensitizer. With this approach, 85% (local lymph node assay) and 93% (human) of non-sensitizer predictions were correct, whereas the "two out of three" approach had 69% (local lymph node assay) and 79% (human) of non-sensitizer predictions correct. The findings are consistent with the argument, supported by published quantitative mechanistic models that only the first KE needs to be modeled. All three assays model this KE to an extent. The value of using more than one assay depends on how the different assays compensate for each other's technical limitations.

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Human-Derived In Vitro Models Used for Skin Toxicity Testing Under REACh

Kolle

Landsiedel

2020

Organotypic Models in Drug Development

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Peptide reactivity associated with skin sensitization: The QSAR Toolbox and TIMES compared to the DPRA

Cited by 32 publications

References 36 publications

Assessment of Pre- and Pro-haptens Using Nonanimal Test Methods for Skin Sensitization

Assessment of Pre- and Pro-haptens Using Nonanimal Test Methods for Skin Sensitization

Non‐animal assessment of skin sensitization hazard: Is an integrated testing strategy needed, and if so what should be integrated?

Human-Derived In Vitro Models Used for Skin Toxicity Testing Under REACh

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