ToxSci Advance Access published online on September 26, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg242
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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1 Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, UK
* To whom correspondence should be addressed. E-mail: m.h.abraham{at}ucl.ac.uk.
Draize rabbit eye test scores, as modified maximum average score, MMAS, for 68 pure bulk liquids were adjusted by the liquid saturated vapor pressure P°. These 68 adjusted scores, as log (MMAS/P°), were shown to be completely equivalent to eye irritation thresholds, EIT expressed as log (1/EIT), for 23 compounds in humans. Thus for the first time the Draize eye test in rabbits for pure bulk liquids is shown to be perfectly compatible with eye irritation thresholds in humans. The total data set for 91 compounds was analyzed by the general solvation equation of Abraham. Values of log (MMAS/P°) or log (1/EIT) could be fitted to a five-parameter equation with R2 = 0.936, SD = 0.433, AD = 0.000, and AAD = 0.340 over a range of 9.6 log units. When divided into a training set of 45 compounds, the corresponding equation could be used to predict the remaining 46 compounds in a test set with AD = -0.037 and AAD = 0.345 log units. Thus the 91 compound equation can now be used to predict further EIT values to around 0.4 log units. It is suggested that the mechanism of action in the Draize test and in the human eye irritation thresholds involves passive transfer of the compound to a biophase that is quite polar, is a strong hydrogen bond base, a moderate hydrogen bond acid and quite hydrophobic. The biophase does not resemble water or plasma, but resembles an organic solvent such as N-methylformamide.
© 2003 Society of Toxicology
In Vitro Toxicology and Alternative Testing
Is the Draize Rabbit Eye Test Compatible with Eye Irritation Thresholds in Humans? A Quantitative Structure-Activity Relationship Analysis
2 Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, UK; Department of Chemistry, Sharif University of Technology, Azadi Street, Tehran, Iran
3 Department of Chemistry, Sharif University of Technology, Azadi Street, Tehran, Iran
4 Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, UK; School of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
5 Chemosensory Perception Laboratory, Department of Surgery (Otolaryngology), University of California, San Diego, Mail Code 0957, La Jolla, CA 92093-0957, USA
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