Mode of Action (MOA) Assignment Classifications for Ecotoxicology: An Evaluation of Approaches.

A Kienzler,S E Belanger,A Beasley,M G Barron,M R Embry

doi:10.1021/acs.est.7b02337

A Kienzler, S E Belanger + Show 3 more

Open Access

https://doi.org/10.1021/acs.est.7b02337

Copy DOI

Abstract

The mode of toxic action (MOA) is recognized as a key determinant of chemical toxicity and as an alternative to chemical class-based predictive toxicity modeling. However, MOA classification has never been standardized in ecotoxicology, and a comprehensive comparison of classification tools and approaches has never been reported. Here we critically evaluate three MOA classification methodologies using an aquatic toxicity data set of 3448 chemicals, compare the approaches, and assess utility and limitations in screening and early tier assessments. The comparisons focused on three commonly used tools: Verhaar prediction of toxicity MOA, the U.S. Environmental Protection Agency (EPA) ASsessment Tool for Evaluating Risk (ASTER) QSAR (quantitative structure activity relationship) application, and the EPA Mode of Action and Toxicity (MOAtox) database. Of the 3448 MOAs predicted using the Verhaar scheme, 1165 were classified by ASTER, and 802 were available in MOAtox. Of the subset of 432 chemicals with MOA assignments for each of the three schemes, 42% had complete concordance in MOA classification, and there was no agreement for 7% of the chemicals. The research shows the potential for large differences in MOA classification between the five broad groups of the Verhaar scheme and the more mechanism-based assignments of ASTER and MOAtox. Harmonization of classification schemes is needed to use MOA classification in chemical hazard and risk assessment more broadly.

Highlights

There has been a shift in the risk assessment paradigm toward a more mechanistically based understanding of the mechanism and mode of action of chemicals.[1]
The data set of 3448 chemicals was evaluated using Ecological Structure Activity Relationships (ECOSAR) to provide an overview of the chemical class coverage
One of the most significant barriers to the use of mode of toxic action (MOA) assignment tools is the high number of errors found in the database associated with the assignment of unique Chemical Abstracts Service numbers (CAS)

Summary

Introduction

There has been a shift in the risk assessment paradigm toward a more mechanistically based understanding of the mechanism and mode of action of chemicals.[1]. Various structure-based classification schemes have been developed to categorize chemicals based on the mode of toxic action (MOA). The various MOA classification schemes provide information on a key determinant of chemical toxicity and as an alternative to chemical class-based predictive toxicity modeling. Direct regulatory application of these MOA classifications has been seen most directly in chemical classification and in the use of Quantitative Structure−Activity Relationship (QSAR) models in risk assessment.[6] MOA plays a role in mixture risk assessment, where both the grouping of chemicals and the choice of the concentration addition or independent action hypothesis can be based on knowledge of the MOA.[7]

Objectives

Methods

Results

Conclusion