title: Peptide reactivity associated with skin sensitization: The QSAR Toolbox and TIMES compared to the DPRA.
abstract: The molecular initiating event (MIE) of skin sensitization is the binding of a hapten to dermal proteins. This can be assessed using the in chemico direct peptide reactivity assay (DPRA) or in silico tools such as the QSAR Toolbox and TIMES SS. In this study, the suitability of these methods was analyzed by comparing their results to in vivo sensitization data of LLNA and human studies. Compared to human data, 84% of non-sensitizers and sensitizers yielded consistent results in the DPRA. In silico tools resulted in 'no alert' for 83%-100% of the non-sensitizers, but alerted only 55%-61% of the sensitizers. The inclusion of biotic and abiotic transformation simulations yielded more alerts for sensitizers, but simultaneously dropped the number of non-alerted non-sensitizers. In contrast to the DPRA, in silico tools were more consistent with results of the LLNA than human data. Interestingly, the new "DPRA profilers" (QSAR Toolbox) provided unsatisfactory results. Additionally, the results were combined in the '2 out of 3' prediction model with in vitro data derived from LuSens and h-CLAT. Using DPRA results, the model identified 90% of human sensitizers and non-sensitizers; using in silico results (including abiotic and biotic activations) instead of DPRA results led to a comparable high predictivity.
authors.affiliation: BASF SE, Experimental Toxicology and Ecology, Ludwigshafen, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Urbisch
authors.affiliation: BASF SE, Experimental Toxicology and Ecology, Ludwigshafen, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Honarvar
authors.affiliation: BASF SE, Experimental Toxicology and Ecology, Ludwigshafen, Germany.
authors.forename: S N
authors.initials: SN
authors.lastname: Kolle
authors.affiliation: BASF Personal Care and Nutrition GmbH, Düsseldorf, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Mehling
authors.affiliation: BASF SE, Experimental Toxicology and Ecology, Ludwigshafen, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Ramirez
authors.affiliation: BASF Schweiz AG, Basel, Switzerland.
authors.forename: W
authors.initials: W
authors.lastname: Teubner
authors.affiliation: BASF SE, Experimental Toxicology and Ecology, Ludwigshafen, Germany. Electronic address: robert.landsiedel@basf.com.
authors.forename: R
authors.initials: R
authors.lastname: Landsiedel
mesh_terms: D000818:Animals; D002074:Butanones / Q000633:toxicity; D047188:Chalcones / Q000633:toxicity; D003198:Computer Simulation; D003512:Cyclohexanones / Q000633:toxicity; D017449:Dermatitis, Allergic Contact / Q000378:metabolism*; D005663:Furans / Q000633:toxicity; D006241:Haptens / Q000633:toxicity*; D006801:Humans; D023441:Local Lymph Node Assay; D051379:Mice; D008962:Models, Theoretical; D010455:Peptides / Q000378:metabolism*; D011485:Protein Binding; D011773:Pyruvates / Q000633:toxicity; D021281:Quantitative Structure-Activity Relationship
chemical_list: D002074:Butanones; D047188:Chalcones; D003512:Cyclohexanones; D005663:Furans; D006241:Haptens; D010455:Peptides; D011773:Pyruvates; C511839:alpha-furil; C104813:methyl pyruvate; C477259:2-acetylcyclohexanone; C035851:benzoylacetone; C100349:1-phenyl-1,2-propanedione
keywords: Direct peptide reactivity assay (DPRA); In chemico; In silico; Protein binding; Quantitative structure–activity relationship (QSAR); Skin sensitization