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

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.