of yes or no. The use of retinoid creams for dermal application can serve as an example. Retinoids were already known to cause developmental toxicity in pregnant animals of every test species examined. The regulatory decision concerning retinoid creams for dermal application was based on barely detectable changes in the blood concentrations of endogenous retinoids after dermal application of the drug. However, there is still minimal marketing of retinoid creams for dermal application. A similar case has been noted for vitamin A pills (retinyl palmitate) administered at doses greater than 30,000 IU per day (R.K. Miller et al. 1998).
If data show that a chemical is absorbed into the systemic circulation, then the next most important piece of toxicokinetic information is a determination of whether the biologically active toxicant is the parent compound, a metabolite, or both. Without such knowledge, the usefulness of other toxicokinetic data is diminished. If the active toxicant is not clearly delineated, then the qualitative and quantitative metabolic patterns that often vary between species for the agent of interest cannot be constructively applied in the characterization of hazard and the management of potential risks.
A determination of species concordance in susceptibility, in both basic research studies and developmental toxicity hazard assessment testing of chemical agents, is often the key element that provides the foundation for a generalization of the findings and extrapolations relevant for humans. Toxicokinetics are therefore studied to compare absorption, distribution, metabolism, and elimination of the test agent and its relevant metabolites. Toxicokinetic measurements can be used to determine the internal dose delivered to target tissues rather than relying on the administered dose, thereby taking into account species differences and individual variations in the extent and duration of systemic exposure in maternal and conceptus compartments. These interspecies variations and the interindividual differences in the same species indicate that each individual has a specific “fingerprint” of unique alleles of genes encoding drug-metabolizing enzymes (DMEs) as well as receptor and transcription factors that regulate the expression of genes encoding those DMEs. All DMEs appear to have endogenous substrates and are used in the biological functions of the normal animal or human, yet these enzymes have specificities that are sufficiently broad to metabolize endogenous substrates and environmental agents (Nebert 1994). Extrapolating toxicokinetic results from laboratory animals to nonhuman primates and humans is further complicated by the fact that the DMEs in the embryo and fetus differ considerably from one another with species-specific temporal patterns of expression observed throughout gestation and postnatal periods (Miller et al. 1996; Cresteil 1998). Such differences can allow drug-metabolizing reactions to occur in primates that are not yet functional in the common laboratory animal conceptus. The significance of such differences is magnified when considered with the differences in the susceptibility between the conceptus and adult tissues.
Few studies have been conducted in pregnant animals that have compared species-specific toxicokinetics. The data collected make it apparent that inter-