The urgency for optimization and harmonization of thyroid hormone analyses and their interpretation in developmental and reproductive toxicology studies.

In recent years several OECD test guidelines have been updated and some will be updated shortly with the requirement to measure thyroid hormone levels in the blood of mammalian laboratory species. There is, however, an imperative need for clarification and guidance regarding the collection, assessment, and interpretation of thyroid hormone data for regulatory toxicology and risk assessment. Clarification and guidance is needed for 1) timing and methods of blood collection, 2) standardization and validation of the analytical methods, 3) triggers for additional measurements, 4) the need for T4 measurements in postnatal day (PND) 4 pups, and 5) the interpretation of changes in thyroid hormone levels regarding adversity. Discussions on these topics have already been initiated, and involve expert scientists from a number of international multisector organizations. This paper provides an overview of existing issues, current activities and recommendations for moving forward.

Effects of the Oral Oxytocin Receptor Antagonist Tocolytic OBE001 on Reproduction in Rats.

BACKGROUND: OBE001 is a novel, orally active nonpeptide oxytocin receptor antagonist under development for the treatment of preterm labor and improvement in embryo implantation and pregnancy rate in assisted reproductive technology (ART). The reproductive safety of OBE001 was evaluated in customized fertility embryonic development (FER)/early embryonic development (EED) and fetal development (FD) and pre/postnatal development (PPN) studies mimicking clinical exposure scenarios. METHODS: Oral OBE001 was evaluated at doses of 37.5, 75, and 125 mg/kg/d in female rats during a FER/EED study (from premating to implantation) and throughout FD during a FD/PPN study. RESULTS: No OBE001 effects were observed during the FER/EED study. The FD/PPN study did not result in adverse OBE001 effects in females allowed to litter, their offspring, and second-generation fetuses. Females at 125 mg/kg/d who underwent cesarean section before term had slight reductions in body weights and food consumption, and associated fetuses had slightly delayed ossification of skull bones, which was not adverse in the absence of effects on live offspring. CONCLUSION: OBE001 at up to 125 mg/kg/d had no effects on EED and no adverse effects on FD and postnatal development of rats. These results constitute an important step toward the development of OBE001 in preterm labor and ART indications.