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The relationship of maternal and fetal toxicity in developmental toxicology bioassays with notes on the biological significance of the "no observed adverse effect level".
Citation:
CHERNOFF, N., E. H. ROGERS, M. I. GAGE, AND B. FRANCIS. The relationship of maternal and fetal toxicity in developmental toxicology bioassays with notes on the biological significance of the "no observed adverse effect level". REPRODUCTIVE TOXICOLOGY. Elsevier Science Ltd, New York, NY, 25(2):192-202, (2008).
Impact/Purpose:
One of the most basic issues in risk assessment of developmental toxicology bioassays is the relationship of the mandated maternal toxicity and fetal responses. Previous attempts to determine this have not been successful given the complexity of the maternal and fetal toxic responses, and the fact that attempts to survey the published literature have to deal with a wide variety of experimental designs, laboratory animal strains, and differences in maternal and fetal evaluations. The current paper approached the problem by analysis of 125 developmental toxicology studies done for the National Toxicology Program over a 22 year period. Our analysis indicates that in a large majority of the rodent studies the single criterion used to determine the LOAELs in both maternal and fetal systems is reduced weight. Reduced fetal weight at birth is considered a manifestation of developmental toxicity. Examination of periods of maternal weight loss during gestation and fetal effects at term shows that fetal weight reduction is highly associated with maternal weight loss occurring late in gestation. This maternal weight loss, in turn, is due to reduced food intake. Reduced food intake occurs from exposure to an extremely diverse group of agents and is most probably due to general toxicity. The reduced maternal food intake will result in intrauterine growth retardation and reduced fetal weight at term. The most susceptible period of development will be late in gestation when fetal growth is greatest while it is apparent that maternal weight loss occurring only early in gestation does not generally cause fetal weight changes at term. The conclusion that may be drawn is that agents that disrupt maternal food consumption (e.g. by nausea, lethargy, or reduced palatability of the diet or drinking water) may result in fetal effects only through general maternal toxicity. Referring to these agents as developmental toxicants may be inappropriate and decisions based on reduced fetal weight noted only in conjunction with reduced maternal weight may not be toxicologically defensible. The data summarized in this paper indicate that regulatory agencies such as the E.P.A. should re-evaluate the criteria used to classify an agent as “developmentally toxic”. The paper also suggests experimental approaches to testing this idea – an approach that may be desirable both for general risk assessment and for specific agents with useful applications that may be inappropriately banned from use.
Description:
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.
