Citation:

Rogers, J. Regulatory Perspective on Evaluation and Interpretation of Effects on Skeletal Development, and Outlook for the Future- Abstract. Society of Toxicology, Baltimore, Maryland, March 10 - 14, 2019.

Impact/Purpose:

This abstract is for a lecture on normal and abnormal skeletal development and how skeletal development is assessed for regulatory decision making.

Description:

Many chemically-induced skeletal malformations have been described and accepted as teratogenic effects. Other skeletal effects observed in term fetuses, such as increases in common skeletal variants, reduced ossification of skeletal elements, and bent or wavy bones, present a more complex interpretation. These skeletal effects are often associated with maternal toxicity (e.g., supernumerary lumbar rib [SNR]), lower fetal weight (e.g., reduced ossification) or may be transient (e.g., reduced ossification, bent or wavy bony structures). Guidelines from regulatory bodies indicate that such associations or transience may reduce concern for teratogenicity, but still regard such effects as developmental toxicity when dose-responsive. Several investigations have demonstrated a bimodal distribution of SNR length in rats and mice, and have suggested that the longer SNR are more likely to be chemically induced while the shorter SNR are background variants. Double-staining bone and cartilage differentiates missing and unossified skeletal elements; reduced ossification of elements known to be ossified late in gestation (e.g., distal phalanges, sternebrae and calvaria) likely represents developmental delay, often with lower fetal weight. Postnatal observations have demonstrated complete ossification of these structures. However, reduced ossification in unusual patterns, in bones normally well-ossified at term, or not associated with lower fetal weight is of higher concern. Wavy ribs are common in rodent fetuses, and can occur along with bent long bones and/or bent scapulae. Studies comparing wavy rib occurrence in fetuses vs. neonates indicate that this effect may be transient. Importantly, interpretation of skeletal anomalies must be made in the context of other maternal and fetal findings. Looking forward, elucidation of molecular underpinnings of skeletal development will inform development of mechanistic adverse outcome pathways (AOPs) for skeletal anomalies, and AOPs can provide biological plausibility for development of in vitro assays using human cells to predict effects on skeletal development. Three-dimensional organ-on-chip models using human stem cells may be used for mechanistic developmental toxicology. This abstract does not represent EPA policy.

Record Details: