You are here:
Maternal and fetal toxicity in developmental toxicology bioassays: Weight changes and their biological significance
Citation:
CHERNOFF, N., E. H. ROGERS, AND M. GAGE. Maternal and fetal toxicity in developmental toxicology bioassays: Weight changes and their biological significance. Presented at Teratology, Monterey, CA, June 28 - July 05, 2008.
Impact/Purpose:
Presentation @ Teratology Meeting
Description:
Standard developmental toxicology bioassays are designed to identify agents with the potential to induce adverse effects in the embryo/fetus. Guidelines call for the inclusion of a dose level(s) that induces “overt maternal toxicity.” The possibility that general maternal toxicity can affect development has lead to attempts to define general relationships between maternal and developmental endpoints. This study constitutes an analysis of 125 rat, mouse and rabbit developmental toxicity bioassays conducted by the National Toxicology Program from 1981 to 2003. The data indicate that weight is a highly significant factor in determining both maternal and fetal Lowest Observed Adverse Effect Levels (LOAELs). Maternal LOAELs were determined by reduced gestational weight (wt) gain 'alone' in 60% of mouse and ≥80% of rat and rabbit studies (the percentages are ≥86% in all species at dose levels where another toxic effect was also noted). Fetal LOAELs were set by reduced term wt alone in 71% of rat, 82% of mouse and 11% of rabbit studies. For specific dose groups in the studies examined, correlation of fetal and maternal wt reductions varied between species; significant correlations were noted in the rat (p<0.05), and mouse, (p<0.01), but were n.s. in the rabbit. Analysis of maternal and fetal wts in the rat shows that the time of maternal wt loss during gestation is a major determinant in the fetal response. Significant fetal wt reductions at term in the rat occurred in 82% dose levels where maternal wt reductions were noted after GD15 as compared to 16% in studies where maternal wt changes only occurred before GD15. The magnitude of reductions in fetal wt and maternal wt gain at term is significantly correlated in both the rat (P>0.01) and mouse (P>0.05). The NTP data indicate that maternal wt reductions are associated with reduced food and/or water intake for a wide variety of dissimilar test agents. It is well known that maternal undernutrition, especially during the period of rapid fetal growth late in gestation, will result in reduced fetal wt at term. This raises the possibility that reported developmental toxicity based on reduced fetal wt at term may, in numerous instances, be due to maternal undernutrition caused by agent-induced general toxicity rather than any direct developmental insult. Consequently, such test agents may be erroneously classified as primary developmental toxicants. The analysis reported here indicates the need for paired feeding studies to determine to what extent observed fetal wt changes are due to maternal undernutrition, in contrast to a direct toxic action on the developing embryo/fetus.