The toxicokinetic patterns that have been important in discriminating developmental toxicity are described here in terms of AUC and Cmax, and not in terms of metabolite profile (i.e., the qualitative similarities in a parent compound and its metabolites). Species are known to differ in the rates that they absorb, distribute, and excrete compounds (i.e., the metabolic rate manifested at AUC and Cmax). Pharmaceutical studies have demonstrated that metabolite profiles between species are often similar (Nau et al. 1994), and this similarity is one of the reasons that it is common practice to use various animal models to assess the potential toxicity of chemicals. The committee will later propose that human DME genes be introduced into model animals to further reduce differences in metabolism. These transgenic animals are likely to have similar metabolite profiles as humans but will be considerably different from humans in terms of metabolic rate.
In summary, the correct application of toxicokinetic information in the determination of hazard and in judgments concerning risk characterization requires a broad view of pharmacological, toxicological, and embryological principles. These principles have guided the committee in their considerations on how most effectively to incorporate recent advances in molecular and developmental biology in risk assessment.
As the committee has outlined in the previous sections of this chapter, key challenges facing risk assessors include the need to understand critical initial events caused by toxicants (events that occur at low doses and early stages of toxicity) and to understand the implications of animal toxicity for human health. Ideally, appropriate biomarkers could serve as indicators to link exposure and early biological effects, and ultimately link those early effects with disease or pathogenesis. As numerous NRC reports have indicated, biomarkers of exposure, effects, and susceptibility are exactly the types of indicators that are needed to address these risk assessment challenges.
Specifically, biomarkers for developmental toxicity have been reviewed in the context of reproductive toxicology in a previous NRC (1989) report, Biologic Markers in Reproductive Toxicology. Three types of biomarkers have been defined (NRC 1989):
A biologic marker of exposure is an exogenous substance or its metabolite(s) or the product of an interaction between a foreign chemical and some target molecule or cell. The biomarker is measured in a compartment within an organism.
A biologic marker of effect represents a measurable biochemical, physiological, or other alteration within an organism that, depending on magnitude, can be recognized as causing an established or potential health impairment or disease.