tigations already completed. In this context, the committee needs to point out some serious shortcomings in the present approaches to interspecies extrapolations of toxicokinetic information, particularly those extrapolations that make the jump from laboratory animals to pregnant women. All too often, toxicokinetic data from pregnant animals are collected only for the maternal organism, and equally important aspects of the conceptus compartments are entirely lacking. As the examples of some chemicals studied in more detail have shown, the maternal-conceptus kinetics of chemicals and drugs change dynamically throughout gestation. Pharmacokinetic measurements in human pregnancy related to therapeutically used pharmaceutical agents are typically derived from blood and tissue samples collected from term deliveries and constitute only one or just a few time points after the drug’s administration. Many significant changes occur throughout gestation that can make such term kinetic assessments less directly applicable for evaluation of first-trimester exposures.

The present dosing regimens in safety evaluations do not always consider the profound differences in elimination half-lives of chemicals between animal test species and humans (Nau 1986). The studies on valproic acid revealed dramatic species differences in the toxicokinetics of this drug that correlate with the species-specific teratogenic response (Nau 1986). Technical means of dosing that overcome the toxicokinetic differences between humans and pregnant animals exist and have been shown to be applicable and useful. For example, the studies on valproic acid were conducted by subcutaneously implanting osmotic mini-pumps that can deliver a chemical at a constant rate and produce maternal serum pharmacokinetic profiles with concentrations of the test chemical that resemble those occurring in humans much more closely than single or even repeated bolus administrations (Nau et al. 1981, 1985). However, conventional developmental toxicity testing designs still do not use that methodology routinely. It was critical for the committee to consider these factors in their deliberations on how to use new biological information for human risk assessment. Toward that end, it will be helpful to understand whether a developmental toxicant acts by exceeding a certain threshold peak concentration (Cmax) for a brief period of time, or whether an extended exposure to a certain concentration of the chemical over some period of time, is required to induce abnormal development. Such toxicokinetic relationships are graphically expressed as a plot of the concentration of the chemical of concern in maternal plasma (and preferably also in the embryo) against time. This visual display of the chemical-analytical presence of the substance and time is commonly known as area under the curve (AUC), as shown in Figure 3-3. In developmental toxicity studies, both the Cmax and the AUC concepts have been all too uncritically applied in assessing the value of toxicokinetics in pregnancy. The maternal AUC has often been used to draw conclusions about the chemical exposure of the conceptus without the availability of any toxicokinetic information from the conceptus compartments. The assessment of conceptus toxicant levels can be invaluable for understanding animal species differences in develop-

The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement