TABLE 1

Glossary of terms

TermDefinition
AOP“An AOP is a conceptual construct that portrays existing knowledge concerning the linkage between a direct molecular initiating event (e.g., a molecular interaction between a xeno-biotic and a specific biomolecule) and an adverse outcome at a biological level of organization relevant to risk assessment.”a
MOAA “biologically plausible series of key events leading to” an adverse effect.b
A “sequence of Key Events and processes, starting with interaction of an agent with a cell, proceeding through operational and anatomical changes, and resulting in” an adverse effect. “Mode of action is contrasted with ‘mechanism of action,’ which implies a more detailed understanding and description of events.”c
KE“A key event is an empirically observable step or its marker, which is a necessary element of the mode of action critical to the outcome (i.e., necessary, but not necessarily sufficient in its own right); key events are measurable and reproducible.”b
Measureable/observable biologic changes that are essential to the progression from the molecular interaction of a xenobiotic with the biologic system to an AO considered relevant to regulatory decision making. “KEs are, in essence, measurements of biological state or change in state with regard to a control or reference. Because KEs are measurements or observations of state, the confidence one has in a KE is dictated by the accuracy and precision with which that biological state can be measured.”d
KERThe predictive and/or causal linkages between a pair of KEs. “KERs, in contrast, are a unit of inference or extrapolation. They are defined by the biological plausibility and evidence that provide a scientifically credible basis for inferring or predicting the state of a downstream KE based on the known state of an upstream KE and the confidence in that inference or prediction is defined by the weight of supporting evidence.”d
MIEThe first KE within an AOP representing the biologic perturbation resulting from a molecular interaction between a xenobiotic and a specific biomolecule.
AOLate stage KE in an AOP representing a biologic perturbation that would be considered adverse in a regulatory context. These typically occur at either the individual (e.g., cancer) or population (e.g., lack of reproductive carrying capacity) levels of organization.
  • a Ankley et al. (2010).

  • b Meek et al. (2014a).

  • c EPA (2005).

  • d Villeneuve et al. (2014a).