Numeric Estimates of Teratogenic Severity from Embryo-Fetal Developmental Toxicity Studies.

A developing organism exposed to a toxicant will have a response that ranges from none to severe (i.e., death or malformation). The response at a given dosage may be termed teratogenic (or developmental toxic) severity and is dependent on exposure conditions. Prenatal/embryo-fetal developmental (EFD) toxicity studies in rodents and rabbits are the most consistent and definitive assessments of teratogenic severity, and teratogenesis screening assays are best validated against their results. A formula is presented that estimates teratogenic severity for each group, including control, within an EFD study. The developmental components include embryonic/fetal death, malformations, variations, and mean fetal weight. The contribution of maternal toxicity is included with multiplication factors to adjust for the extent of mortality, maternal body weight change, and other parameters deemed important. The derivation of the formula to calculate teratogenic severity is described. Various EFD data sets from the literature are presented to highlight considerations to the calculation of the various components of the formula. Each score is compared to the concurrent control group to obtain a relative teratogenic severity. The limited studies presented suggest relative scores of two- to <fivefold higher than control have detectable but a low level of teratogenic severity, and scores ≥ fivefold higher than control have increasingly more severe teratogenicity. Such scores may help refine the concept of an exposure-based validation list for use by proponents of screening assays (Daston et al., 2014) by estimating the severity of "positive" exposures, or in other situations by defining the severity of a LOAEL (lowest observed adverse effect level).