Numeric Estimates of Teratogenic Severity from Embryo–Fetal Developmental Toxicity Studies

Abstract

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)

The DevTox Germ Layer Reporter Platform: An Assay Adaptation of the Human Pluripotent Stem Cell Test

“…To test the DevTox GLR-Endo assay predictive performance, a larger set of 58 positive and negative developmental toxicants identified from benchmark sets used to evaluate the hPST and devTOX quick Predict assays were selected [ 47 , 52 ] ( Table S1 ). Chemicals from the hPST benchmark set were selected to enable direct comparison of SOX17-dependent changes in the hPST, while chemicals from the devTOX quick Predict benchmark set comprised a more general set of compounds used to evaluate other in vitro developmental toxicity assays [ 28 , 39 , 70 , 72 , 73 ]. Chemicals were tested at concentrations ranging from 1 pM to 200 µM, skewed towards the upper end of the concentration series.…”

Maternotoxicity and fetotoxicity in Rattus norvegicus albinus exposed to tramadol during the late phase of pregnancy

“…Teratologic abnormalities are scarcely diagnosed early in the life although; these are present at birth (Wise, 2016). In the perinatal period, congenital deformities are responsible for approximately 18-20% stillbirths.…”

“…Moreover, malformation in 2-3% new born infants are the most likely diagnosed while another 3-5% abnormalities are spotted later in the life (Sadler, 2011). Response of growing embryo (i.e., death or disfigurement) to toxicant is principally dependent upon the dosage of the toxicant and the route and duration of exposure (Wise, 2016). Etiologies of congenital abnormalities are diverse and include but not limited to a sequence of environmental and hereditary causes (65-75%), single gene defects and chromosomal irregularities (20-25%) and exposure to medicines, toxins, and mechanical force (3-4%) (Schaefer, Peters, & Miller, 2014).…”

Teratogenicity and Teratogenic Factors

“…This response at a given dosage is sometimes defined as teratogenic (or developmental toxic) severity and is dependent on exposure conditions. 2 The factors that induce congenital malformations are termed the "teratogenic factors"; they include infectious, physical, chemical, hormonal, and maternal health factors.…”