Maternal factors

A further aspect that needs consideration is the interaction between the mother and conceptus. It is clear that this interaction is not immediately included in the DTO. The strength of the in vitro/in silico assays is considered by many to be the absence of the confounding influence of maternal organism/placenta. This influence may in some cases be a confounder in animal (in vivo) testing, i.e. masking the potential intrinsic developmental toxicity of a compound by species-specific, high maternal toxicity. However, the intact interaction of mother and conceptus also is an essential component of risk assessment, taking into account bioavailability, metabolism and placental transfer. Moreover, some additional factors, such as the availability of essential nutrients necessary for development may also be influenced, leading to toxicity, which can only be identified in vivo.

Thus, for risk assessment, the role of the mother, frequently condensed in the term “maternal toxicity”, needs to be considered and is an essential component in an IATA. The presence of the mother and placenta are major strengths of the intact animal tests because the exposure of the human conceptus to potential insult is indeed via the mother, through the placenta; absorption, distribution, metabolism, and elimination of the chemical in the mother and in the placenta determine and control the exposure of the conceptus — when it is exposed, and how long it is exposed. The health of the mother affects the growth and development of the conceptus(es) in utero, the success of delivery, and the continued postnatal growth and development of the offspring neonatally, during the lactational period and beyond. The term “maternal toxicity” covers a variety of maternal effects which may or may not affect development, depending on the mode/mechanism of action of the chemical, the dose, the severity of the effect(s), and the timing of exposure. Information on the interactions between the mother and the conceptus may also provide answers on how KEs in the cascade of developmental processes are regulated, or whether they are perturbed or delayed by “outside events”, or whether there are interactions between different AOPs.

Advances in the prediction of in vivo developmental toxicity have been made by combining an in vitro model using embryonic stem cells with a simple in vitro model for placental transfer (Li et al., 2015). This demonstrates the importance of maternal factors (such as the placental barrier function) but also indicates the possibility to include these in a more complex model. Physiologically-based pharmacokinetic (PBPK) modelling should be an essential part of the final risk assessment. However, by itself, PBPK modelling only describes the concentration of the compound causing developmental toxicity, and is not a DTO per se. Some other maternal factors, such as the transport and availability of (micro)nutrients, stress hormones, and oxygen, can be direct-acting developmental toxicants and would need to be taken into account at some stage.