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Structure-Potency Relationships for Epoxides in Allergic Contact Dermatitis.
David W Roberts1, Aynur Aptula2, Anne Marie Api3
1School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University , Liverpool L3 3AF, United Kingdom.
Chemical Research in Toxicology
|January 26, 2017
Summary
This study developed a quantitative mechanistic model (QMM) to predict skin sensitization potency for epoxides. The model uses reaction kinetics and hydrophobicity to assess chemical reactivity, aiding in risk assessment.
Area of Science:
- Chemical toxicology
- Computational chemistry
- Dermatology
Background:
- Epoxides are implicated in skin sensitization via direct exposure or formation from other chemicals.
- Epoxides function as SN2 electrophiles, but quantitative models for their sensitization potency are lacking.
Purpose of the Study:
- To develop a quantitative mechanistic model (QMM) for predicting epoxide skin sensitization potency.
- To establish a correlation between chemical reactivity and in vivo sensitization data.
Main Methods:
- Combined experimental kinetic data (rate constants) with calculated hydrophobicity (logP).
- Derived a relative alkylation index (RAI) as logk + 0.4 logP.
- Developed a QMM correlating RAI with local lymph node assay (LLNA) EC3 values.
Main Results:
- A QMM equation (pEC3 = 2.42(±0.26) RAI + 4.04 (±0.25)) was derived, fitting 9 data points with high R-squared (0.928).
- One outlier was identified and rationalized by potential oxidation to a highly reactive aldehyde.
- The model accurately predicted the potency of a non-epoxide SN2 electrophile.
Conclusions:
- The developed QMM effectively predicts skin sensitization potency for epoxides.
- The model shows potential for broader application to H-polar SN2 electrophiles.
- This QMM can be a valuable tool for skin sensitization risk assessment.
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