ABSTRACT
Maternally-Mediated Effects Defined In standard Segment II mammalian bioassays for developmental toxicity, it is the pregnant animal that is exposed to the test article, so in this sense, all in utero developmental toxicity is mediated by the mother. This will include absorption, distribution, metabolism, and excretion of administered chemicals, but may also include pharmacodynamic effects on the mother. In this chapter, we define maternally-mediated effects on development as those adverse consequences to the developing conceptus that occur secondarily as a result of an untoward effect on the pregnant mother. They differ from direct effects on the conceptus primarily in their immediate source, rather than the end result. Since likely mechanisms for maternally-mediated effects are more limited in number than are direct-acting mechanisms, the range of consequences to the offspring may also be more limited. Nevertheless, as pointed out by Daston (1), because there are multiple mechanisms by which maternally-mediated effects may occur, it is unlikely that they would result in a consistent, limited spectrum of effects on the offspring. The potential for maternally-mediated developmental toxi-
city makes the task of extrapolating from animal data to potential human outcomes more problematic (1,2). As stated by Kimmel and colleagues (3), “The developing mammal and its maternal support system present a special situation in toxicology and risk assessment.” They recognized that the nurturing maternal environment offers a degree of protection against at least some environmental perturbations, but that factors disturbing that environment may adversely affect development. While it is well established that fetal disruptions can be maternally mediated, questions remain regarding the kinds of effects produced, their prevalence, and their biological and toxicological significance (1,4). It is likely that fetal malformations, functional alterations, growth retardation, and deaths can result from direct effects on the fetus, indirect (maternally-mediated) effects, or a combination of the two (5). Interpretation of concomitant maternal and developmental toxicity is difficult, and presumptions that the two are linked are unwarranted without further studies. A reasonable approach is that of Chernoff and coworkers (2), who advocate concern about developmental toxicity whether or not there is concurrent maternal toxicity, unless there is unequivocal evidence that humans would not be similarly affected. Understanding of the dose response for maternal and developmental toxicity as well as the underlying etiology of the developmental toxicity is required to make that determination.
