these assessments are chemical structure-activity information, in vitro assessments, in vivo animal bioassays, and epidemiological studies. Two additional steps in risk assessment, dose-response assessment and exposure assessment, are described. Finally, the use of toxicokinetic information and biomarkers in developmental toxicity risk assessment is discussed.
Information on a chemical’s structure, stability, solubility, reactivity, and electrophilicity can provide useful clues to its potential to be absorbed and distributed throughout the body and to be reactive with biological tissues. In fact, despite early concepts of a true placental barrier, it is now appreciated that all lipid-soluble compounds have access to the developing cells of an embryo and fetus. Properties of lipid solubility and characteristics such as chemical size and pKa can be used to predict the potential for chemicals to cross the placenta and have access to conceptus tissues (Slikker and Miller 1994).
Structure-activity relationships (SARs) are developed to show the relationship between the specific chemical structures or moieties of agents and their capacity to produce certain toxic effects. For glycol ethers, retinoic acid, valproic acid, and their derivatives and for several other commercial products and therapeutics, good SAR data exist for developmental effects. Recently, SARs were reported for valproic acid derivatives that activate the peroxisomal proliferation pathway and cause developmental toxicity (Lampen et al. 1999).
Early research on receptor binding identified SARs for environmental agents such as benzopyrene and dioxin. Toxicity equivalency factors (TEFs) have been developed that relate the relative toxicity of each compound to a reference compound, such as benzo[a]pyrene (B[a]P) or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) for pyrenes and dioxins, respectively (Van den Berg et al. 1998). Complexities arise when different toxicity end points have different SARs. To be useful for developmental toxicity risk assessments, SARs (and TEFs) must be evaluated for each of the end points of developmental toxicity.
Alternatives to pregnant experimental mammals in studies of developmental toxicology have often been grouped together as in vitro approaches, but that is misleading, because they include not only ex vivo mammalian embryos, tissues, cells, and subcellular preparations but also embryos of nonmammalian species. Broadly, such alternatives have had two applications: to test chemicals for potential effects and to analyze mechanisms of effect.
Mechanistic uses of ex vivo methods have much in common with investigative studies in other areas of biology. They have made major contributions to understanding developmental toxicity, because of the manipulations possible in