The relationship of maternal and fetal toxicity in developmental toxicology bioassays with notes on the biological significance of the “no observed adverse effect level”

Standard developmental toxicology bioassays are designed to identify agents with the potential to induce adverse effects and include dose levels that induce maternal toxicity. The work reported here was undertaken to evaluate the relationship of maternal and fetal toxicity. It constitutes an analysis of 125 developmental toxicity bioassays in the mouse, rat, and rabbit conducted by the National Toxicology Program. Although varying by species, general findings include: (1) most lowest observable adverse effect levels (LOAELs) were determined by reduced maternal gestational weight gain or fetal weight at term. (2) Maternal weight reductions are associated with reduced food intake for a variety of dissimilar test agents. (3) Lower fetal weights were associated with reduced maternal weight gains late in gestation. (4) The degree of fetal weight reduction is correlated with the extent of the maternal weight loss. In a substantial number of the studies, reduced fetal weights at term may, therefore, be due to maternal undernutrition caused by general toxicity rather than direct developmental insult. Consequently, such test agents may be erroneously classified as primary developmental toxicants. Experimental approaches to test the hypothesis that maternal undernutrition in standard developmental toxicology bioassays may be responsible for significant term fetal weight decrements are discussed.