ToxSci Advance Access published online on March 30, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm064
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Quantification of Chemical Peptide Reactivity for Screening Contact Allergens: A Classification Tree Model Approach
1 The Procter & Gamble Company, Miami Valley Innovation Center, Cincinnati, OH, 45252, USA 2 Université Louis Pasteur, Laboratoire de Dermatochimie, UMR 7123, Strasbourg, France
Corresponding Address: G. Frank Gerberick, Ph.D., The Procter & Gamble Company, Miami Valley Innovation Center, Cincinnati, OH 45253-8707. Tel: (513) 627-2909, Fax: (513) 627-0400, gerberick.gf{at}pg.com
gerberick.gf{at}pg.com, jeff.vassallo{at}bms.com, foertsch.lm{at}pg.com, price.bb{at}pg.com, chaney.jg{at}pg.com, jplepoit{at}chimie.u-strasbg.fr
Received February 6, 2007; revision received March 13, 2007; accepted March 13, 2007
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Abstract |
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In the interest of reducing animal use, in vitro alternatives for skin sensitization testing are under development. One unifying characteristic of chemical allergens is the requirement that they react with proteins for the effective induction of skin sensitization. The majority of chemical allergens are electrophilic and react with nucleophilic amino acids. To determine whether and to what extent reactivity correlates with skin sensitization potential, 82 chemicals comprising allergens of different potencies, and non-allergenic chemicals were evaluated for their ability to react with reduced glutathione (GSH), or with two synthetic peptides containing either a single cysteine or lysine. Following a 15-minute reaction time with GSH, or a 24-hour reaction time with the two synthetic peptides, the samples were analyzed by HPLC. UV detection was used to monitor the depletion of glutathione or the peptides. The peptide reactivity data were compared with existing Local Lymph Node Data (LLNA) data using recursive partitioning methodology to build a classification tree that allowed a ranking of reactivity as minimal, low, moderate and high. Generally, non-allergens and weak allergens demonstrated minimal to low peptide reactivity, whereas moderate to extremely potent allergens displayed moderate to high peptide reactivity. Classifying minimal reactivity as non-sensitizers and low, moderate and high reactivity as sensitizers it was determined that a model based on cysteine and lysine gave a prediction accuracy of 89%. The results of these investigations reveal that measurement of peptide reactivity has considerable potential utility as a screening approach for skin sensitization testing, and thereby for reducing reliance on animal-based test methods.
Key Words: Allergens; alternatives; skin sensitization; peptide reactivity; prediction model.
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