the conceptus indirectly. In the maternal body, they are subject to potential metabolic alterations (e.g., biotransformations in the liver), distribution, storage, and excretion that either enhance or diminish their potential to affect the conceptus adversely. The net result of all these interventions is that some level of active developmental toxicant is available to cross the placenta and eventually reaches target sites in the conceptus. Although it is frequently assumed that the developmental toxicant must reach targets in the conceptus to disrupt development, it should be noted that adverse effects on growth and development can be mediated indirectly through effects on accessory tissues, such as the yolk sac and placenta, or on maternal tissues.

2. “The final manifestations of abnormal development are death, malformation, growth retardation, and functional disorder.” This principle highlights the now well-known fact that structural malformations are not the only possible outcome after the conceptus is exposed to a developmental toxicant. In fact, it is now known that in many cases the outcomes are interrelated. For example, at a relatively high dose of a developmental toxicant, the conceptus might suffer a high level of cell death that cannot be replenished by available repair and compensatory mechanisms. This, in turn could result in growth retardation if the induced cell death is widespread, and in death of the conceptus if the cell death compromises organ systems essential for viability of the conceptus. At lower doses particular malformations and functional disorders might occur. Which outcome, or combination of outcomes, will occur depends on the dose and chemical characteristics of the developmental toxicant (discussed in the third and fifth principle, respectively) and the developmental stage of the conceptus at the time of exposure (discussed in the fourth principle).

3. “Manifestations of deviant development increase in degree as dosage increases from the no-effect level to the totally lethal level.” Sufficient evidence was available in the 1970s to support the relationship of dose with the incidence of structural malformations, death, and, to a lesser degree, growth retardation. Evidence accumulated since then extends it to functional deficits as well. It is also important to point out that the relationship between dose and response, although monotonic, does not have to be linear. It can be a steep S-shaped curve for developmental toxicants, sometimes going from a no-effect level to maximal effects within a doubling of the dose.

4. “Susceptibility to teratogenic agents varies with the developmental stage at the time of exposure.” The change of susceptibility was originally published by Wilson as a hypothetical curve in which the degree of sensitivity to developmental toxicant-induced structural malformations was low during the pre-implantation phase, maximal during organogenesis, and low during fetal development. This shape of the developmental sensitivity curve reflects results from many stud-



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