National Toxicology Program

The goal of this testing is to identify chemicals that may pose a risk to the unborn children if pregnant women are exposed. Because it is often difficult to ascertain the association between chemical exposure in pregnant women and adverse health effects on their children, the results of well-controlled animal studies are used by regulatory agencies to help set human exposure guidelines.

Chemicals are tested in pregnant animals such as mice, rats, or rabbits for their potential to cause malformations and signs of toxicity during fetal development. Pregnant females are usually exposed to the test agent from implantation of the embryo in the uterus (gestation day 6 in the rodent) to the day before delivery. However, they may be exposed to the chemical throughout pregnancy and, in some cases, offspring are also exposed following birth. In these developmental toxicity studies, dosing of the females can be done by adding the chemical to their food or water, by putting the chemical on the skin, or by introducing the chemical directly into the stomach through a tube. The females are monitored throughout the study for signs of toxicity. Upon necropsy, fetal toxicity is determined by evaluating pre-implantation and post-implantation fetal loss and fetal weight. Fetuses are evaluated for externally visible malformations, as well as malformations of the internal organs and skeleton. The resulting data are compared to the data for untreated fetuses observed for that species in the test laboratory. Since the effect of a chemical exposure on a pregnant animal can be very different from the effect on a non-pregnant animal, a preliminary study is conducted to determine the doses to be used in each developmental toxicity study. Ideally, doses are selected so that a no adverse effect level (NOAEL) and a lowest adverse effect level (LOAEL) can be determined for maternal toxicity and possibly, fetal toxicity. The experimental protocols in general follow FDA segment 2 guidelines for developmental toxicity testing. These guidelines are outlined by EPA Health Effects Test Guidelines OPPTS 870.3700.

Reference

J. Manson Testing of Pharmaceutical Agents for Reproductive Toxicity. Ch 15, pp 379-402. In: Target Organ Toxicology Series. Developmental Toxicology. 2nd Ed. C. Kimmel and J. Buelke-Sam, eds. Raven Press, NY, 1994.