Understanding transfer systems across the placental barrier is key to understanding the fetal exposure to xenobiotics, including maternal medications.

Although other species, such as the rat and rabbit, are used in developmental and reproductive toxicology (DART) testing of non-biological therapeutics, structural, hemodynamic and cellular physiology differences set them apart from humans in considering biopharmaceutical pharmacokinetics (PK). These are important factors to assist in appropriate dose level selection for further fetal toxicology studies, and for dose margin setting for bio-pharmaceutical risk assessments on human fetal exposure. Furthermore, in the advent of ICH S5 (R3) regulation, there are recommendations for the development, standardisation and use of new alternative methods in DART testing, as drug discovery screens for evaluating adverse effects on embryo and fetal development, to replace the rabbit.

Knowledge on the human syncytiotrophoblast barrier, including transcellular transporters, the paracellular route and endocytosis is still in a juvenile phase; whilst the placental endothelium has been exceptionally understudied. Hence, an appreciation of transfer processes in the PK of the human placental barrier is limited in comparison knowledge of the intestine and the blood-brain barriers. However, state of the art imaging is beginning to reveal the true porous nature of the placental syncytium in the human, which may be in common with other species. Advances in bioengineering and applied mathematics are bringing an added wealth of understanding to placental hemodynamics and reshaping how physiologists think about architectural influences on compound specific barrier transfer rates of nutrients, waste products and xenobiotics.