Potential MIEs and KEs for building AOPs and IATA for Developmental Toxicity

Simply defining the level of biological organisation at which the initiating event for toxicity occurs can be a challenge.  As indicated below, some toxicity may be the result of an exogenous chemical interacting with a specific biomolecule, such as a receptor or enzyme, and it is this KE (i.e. sufficient occupancy of the receptor, or inhibition of the enzyme) that is the necessary step to initiate the subsequent cascade of events at the molecular, cellular and tissue level that produce the adverse outcome.  In other cases, the effect may be at the level of the cell, such as a covalently reactive electrophile that has no specific molecular target, but does sufficient damage to many macromolecules within cells that it leads to cell death or dysfunction at a critical developmental stage.  As noted above, even factors external to the embryo, such as placental dysfunction or maternal physiological perturbations (maternal toxicity), which may also have no distinct molecular target, can also be the KE that initiates adverse development. Examples of molecular, cellular, and maternal/placental mechanisms that may be involved in MIEs and KEs in AOPs for developmental toxicity are shown in Figure 4.

Figure 4: Examples of molecular, cellular, and maternal/placental mechanisms that may be involved in MIEs and KEs in AOPs for developmental toxicity