QSAR Study of Skin Sensitization Using Local Lymph Node Assay Data

Adam Fedorowicz,Lingyi Zheng,Eugene Demchuk,Harshinder Singh

doi:10.3390/i5020056

Abstract

Allergic Contact Dermatitis (ACD) is a common work-related skin disease that often develops as a result of repetitive skin exposures to a sensitizing chemical agent. A variety of experimental tests have been suggested to assess the skin sensitization potential. We applied a method of Quantitative Structure-Activity Relationship (QSAR) to relate measured and calculated physical-chemical properties of chemical compounds to their sensitization potential. Using statistical methods, each of these properties, called molecular descriptors, was tested for its propensity to predict the sensitization potential. A few of the most informative descriptors were subsequently selected to build a model of skin sensitization. In this work sensitization data for the murine Local Lymph Node Assay (LLNA) were used. In principle, LLNA provides a standardized continuous scale suitable for quantitative assessment of skin sensitization. However, at present many LLNA results are still reported on a dichotomous scale, which is consistent with the scale of guinea pig tests, which were widely used in past years. Therefore, in this study only a dichotomous version of the LLNA data was used. To the statistical end, we relied on the logistic regression approach. This approach provides a statistical tool for investigating and predicting skin sensitization that is expressed only in categorical terms of activity and nonactivity. Based on the data of compounds used in this study, our results suggest a QSAR model of ACD that is based on the following descriptors: nDB (number of double bonds), C-003 (number of CHR3 molecular subfragments), GATS6M (autocorrelation coefficient) and HATS6m (GETAWAY descriptor), although the relevance of the identified descriptors to the continuous ACD QSAR has yet to be shown. The proposed QSAR model gives a percentage of positively predicted responses of 83% on the training set of compounds, and in cross validation it correctly identifies 79% of responses.

Highlights

The Bureau of Labor Statistics estimates that occupational skin diseases constitute the second largest group of occupational injuries in the U.S [1]
The murine Local Lymph Node Assay (LLNA) has the capacity to provide dose response data that can be used as a standardized continuous scale in the quantitative assessment of skin sensitization
The selection of the classes of molecular descriptors with P-value below 0.01 is hypothesized to have an association with immunological activity measured by Local Lymph Node Assay, where the three dimensional structure recognition of a given antigen is responsible for the immunological response

Summary

Introduction

The Bureau of Labor Statistics estimates that occupational skin diseases constitute the second largest group of occupational injuries in the U.S [1]. Allergic Contact Dermatitis (ACD) may lead to severe recurrent forms of OCD because of longlasting memory of the immune system. ACD, which is an adaptive, T-cell mediated immune response [2], usually develops as a result of repetitive skin exposures to a sensitizing chemical agent. Information that leads to the development of recommended skin exposure limits that would prevent workers from sensitizing overexposures is an important factor impacting public health. A variety of experimental tests have been suggested to assess the skin sensitization potential of a chemical [3]. Many experimental protocols result in a dichotomous conclusion, more appropriate for denial/acceptance decision-making in design and manufacturing of new chemicals rather than for preventive protection of workers occupationally involved with sensitizing chemical agents. The murine Local Lymph Node Assay (LLNA) has the capacity to provide dose response data that can be used as a standardized continuous scale in the quantitative assessment of skin sensitization

Objectives

Methods

Results

Conclusion