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A robust structure-activity relationship (SAR) model for esters that cause skin irritation in humans.

Authors
Smith-JS; Macina-OT; Sussman-NB; Luster-MI; Karol-MH
Source
Toxicol Sci 2000 May; 55(1):215-222
NIOSHTIC No.
20020813
Abstract
A structure-activity relationship (SAR) model has been developed to discriminate skin irritant from nonirritant esters. The model is based on the physicochemical properties of 42 esters that were tested in humans for skin irritation. Nineteen physicochemical parameters that represent transport, electronic, and steric properties were calculated for each chemical. Best subsets regression analysis indicated candidate models for further analysis. Regression analyses identified significant models (p < 0.05) that had variables that were also significant (p < 0.05). These candidate models were evaluated using linear discriminant analysis to determine if the irritant esters could be discriminated from nonirritant esters. The stability of the model was evident from the consistency of parameters among ten submodels generated using multiple random sampling of the database. The sensitivity of the ten models, evaluated by "leave-one-out" cross-validation, ranged from 0. 846 to 0.923, with a mean of 0.885 +/- 0.025 (95% CI). The specificity ranged from 0.615 to 0.923, with a mean of 0.738 +/- 0.06 (CI). Compared with nonirritant esters, irritant esters had lower density, lower water solubility, lower sum of partial positive charges, higher Hansen hydrogen bonding parameter, and higher Hansen dispersion parameter. The results indicate that physicochemical features of esters contribute to their ability to cause skin irritation in humans, and that chemical partitioning into the epidermis and intermolecular reactions are likely important components of the response. This model is applicable for prediction of human irritation of esters yet untested.
Keywords
Models; Esters; Skin-irritants; Humans; Sampling-methods; Dermatitis
Contact
Department of Environmental and Occupational Health, University of Pittsburgh, 260 Kappa Drive, Pittsburgh, PA 15238
CODEN
TOSCF2
Publication Date
20000501
Document Type
Journal Article
Email Address
mhk+@pitt.edu
Fiscal Year
2000
NTIS Accession No.
NTIS Price
Issue of Publication
1
ISSN
1096-6080
NIOSH Division
HELD
Source Name
Toxicological Sciences
State
WV; PA
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